COMPOUNDS

Abstract

This disclosure relates to compounds of formula (I), which are modulators of STING. Also disclosed are pharmaceutical compositions comprising compounds of formula (I) and methods of using compounds of formula (I) in the treatment or prevention of diseases ameliorated by the modulation of STING.

Claims

1. A compound of formula I: ##STR00090## wherein: Y is either (CH.sub.2).sub.n, where n is from 2 to 4, or —CH.sub.2—CH═CH—CH.sub.2—; R.sup.1 and R.sup.11 are independently selected from —C(═O)OH, —C(═O)OR.sup.P1, Br, F, tetrazolyl, oxo-oxadiazolyl and ##STR00091## (2H-triazol-4-yl), where R.sup.P1 is selected from methyl and ethyl; A.sup.1 is CR.sup.A or N; A.sup.2 is CR.sup.B or N; A.sup.3 is CR.sup.C or N; A.sup.4 is CR.sup.D or N; where no more than two of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 may be N; one, two or three of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, I, Me, Et, CF.sub.3, cyclopropyl, cyano, OMe, OEt, CH.sub.2OH, CH.sub.2OMe and OH; the remainder of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are H; A.sup.11 is CR.sup.AA or N; A.sup.12 is CR.sup.BB or N; A.sup.13 is CR.sup.CC or N; A.sup.14 is CR.sup.DD or N; where no more than two of A.sup.11, A.sup.12, A.sup.13 and A.sup.14 may be N; one, two or three of R.sup.AA, R.sup.BB, R.sup.CC and R.sup.DD (if present) are selected from H, F, Cl, Br, I, Me, Et, CF.sub.3, cyclopropyl, cyano, OMe, OEt, CH.sub.2OH, CH.sub.2OMe and OH; the remainder of R.sup.AA, R.sup.BB, R.sup.CC and R.sup.DD, (if present) are H; R.sup.C1, R.sup.C3 and R.sup.C4 are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF.sub.3, CH.sub.2OH, CH.sub.2OMe, C.sub.2-4 alkenyl and C.sub.5heterocyclyl; R.sup.C11, R.sup.C13 and R.sup.C14 are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF.sub.3, CH.sub.2OH, CH.sub.2OMe, C.sub.2-4alkenyl and C.sub.5heterocyclyl; or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof.

2. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein A.sup.11=A.sup.1, A.sup.12=A.sup.2, A.sup.13=A.sup.3, A.sup.14=A.sup.4, R.sup.C13=R.sup.C3, R.sup.C14=R.sup.C4, R.sup.11=R.sup.1.

3. A compound according to either claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, A.sup.3 is CR.sup.C, and A.sup.4 is CR.sup.D.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein A.sup.11 is CR.sup.AA, A.sup.12 is CR.sup.BB, A.sup.13 is CR.sup.CC, and A.sup.14 is CR.sup.DD.

5. A compound according to either claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein the compound is selected from formulae IIIb, IIIc, IIId and IIIe: ##STR00092##

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein one, two or three of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe, the remainder (if present) are H.

7. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are selected from combinations 1-30: TABLE-US-00021 Combination A.sup.1 A.sup.2 A.sup.3 A.sup.4 1 CF CH CH CH 2 CH CBr CH CH 3 CH CCl CH CH 4 CF CCl CH CH 5 CH CH CH CBr 6 CH CH CCl CH 7 CH CF CF CH 8 CH CH CH CH 9 CF CH CF CH 10 CF CH CCl CH 11 CBr CH CH CH 12 CCl CH CH CH 13 N CH CCl CH 14 CH CCl CCl CH 15 CH CF CH CH 16 CH CMe CH CH 17 CH N CH CH 18 CH CH CBr CH 19 CH CH CCF.sub.3 CH 20 CH CH CEt CH 21 CH CH CF CH 22 CH CH CMe CH 23 CH CH C—OMe CH 24 CH CH CCl CCl 25 CH CH CH CF 26 CH CH CH C—OMe 27 CH CH CH N 28 Cl CH CH CH 29 CH CH CCN CH 30 CBr CH CCl CH

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein one, two or three of R.sup.AA, R.sup.BB, R.sup.CC and R.sup.DD, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe, the remainder (if present) are H.

9. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein A.sup.11, A.sup.12, A.sup.13 and A.sup.14 are selected from combinations 1-30: TABLE-US-00022 Combination A.sup.11 A.sup.12 A.sup.13 A.sup.14 1 CF CH CH CH 2 CH CBr CH CH 3 CH CCl CH CH 4 CF CCl CH CH 5 CH CH CH CBr 6 CH CH CCl CH 7 CH CF CF CH 8 CH CH CH CH 9 CF CH CF CH 10 CF CH CCl CH 11 CBr CH CH CH 12 CCl CH CH CH 13 N CH CCl CH 14 CH CCl CCl CH 15 CH CF CH CH 16 CH CMe CH CH 17 CH N CH CH 18 CH CH CBr CH 19 CH CH CCF.sub.3 CH 20 CH CH CEt CH 21 CH CH CF CH 22 CH CH CMe CH 23 CH CH C—OMe CH 24 CH CH CCl CCl 25 CH CH CH CF 26 CH CH CH C—OMe 27 CH CH CH N 28 Cl CH CH CH 29 CH CH CCN CH 30 CBr CH CCl CH

10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein R.sup.C11=R.sup.C1, R.sup.C13=R.sup.C3 and R.sup.C14=R.sup.C4.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein R.sup.C1, A.sup.C3 and R.sup.C4 are selected from combinations 1-4: TABLE-US-00023 Combination R.sup.C1 R.sup.C3 R.sup.C4 1 H H H 2 H H F 3 OMe H H 4 OMe H F

12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein R.sup.C11, R.sup.C13 and R.sup.C14 are selected from combinations 1-4: TABLE-US-00024 Combination R.sup.C11 R.sup.C13 R.sup.C14 1 H H H 2 H H F 3 OMe H H 4 OMe H F

13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein Y is (CH.sub.2).sub.2.

14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, wherein R.sup.1 and R.sup.11 are selected from C(═O)OH, tetrazolyl and oxo-oxadiazolyl.

15. A compound according to any one of claims 1-14, selected from: 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (1) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (2) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(4-bromobenzoic acid) (3) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (4) 2-(2-(1H-Tetrazol-5-yl)phenyl)-1-(2-(2-(2-(2H-tetrazol-5-yl)phenyl)-5-carbamoyl-1H-benzo[d]imidazol-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxamide (5) 1,1′-(Ethane-1,2-diyl)bis(2-(2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (6) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chlorobenzoic acid) (7) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-dichlorobenzoic acid) (8) 1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (9) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoic acid) (10) 2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chloro-3-fluorobenzoic acid) (11) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chloro-3-fluorobenzoic acid) (12) Dimethyl 6,6′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoate) (13) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoic acid) (14) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-difluorobenzoic acid) (15) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (16) 1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (17) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-7-fluoro-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (18) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-iodobenzoic acid) (19.1 and 19.2) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-7-fluoro-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (20) Dimethyl 6,6′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(2-bromobenzoate) (21) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (22) 1,1′-(Ethane-1,2-diyl)bis(2-(2-chloro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (23) 1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-(2H-1,2,3-triazol-4-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (24) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-methylbenzoic acid) (25) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-methylbenzoic acid) (26) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoic acid) (27) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-fluorobenzoic acid) (28) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoic acid) (29.1 and 29.2) 3,3′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))diisonicotinic acid (30) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chloronicotinic acid) (31) 1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (32) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-ethylbenzoic acid) (33) (E)-6,6′-(But-2-ene-1,4-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid (34) 6,6′-(Propane-1,3-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (35) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(2-bromobenzoic acid) (36) 1,1′-(Ethane-1,2-diyl)bis(2-(3,4-dichloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (37) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-(trifluoromethyl)benzoic acid) (38) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (39) 1,1′-(Ethane-1,2-diyl)bis(2-(3-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (40) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-methoxybenzoic acid) (41) 1,1′-(Ethane-1,2-diyl)bis(2-(5-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (42) 1,1′-(Ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (43) 1,1′-(Ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (44) 1,1′-(Ethane-1,2-diyl)bis(2-(2-bromo-4-chloro-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (45) 1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (46) 2-(5-Carbamoyl-1-(2-(5-carbamoyl-2-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)-4-methoxy-1H-benzo[d]imidazol-2-yl)-5-chloro-3-fluorobenzoic acid (47) 1,1′-(Ethane-1,2-diyl)bis(2-(2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (48) 1,1′-(Ethane-1,2-diyl)bis(2-(2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (49) 1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (50) 2-(5-Carbamoyl-1-(2-(5-carbamoyl-2-(2-carboxy-4-cyanophenyl)-4-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)-4-methoxy-1H-benzo[d]imidazol-2-yl)-5-cyanobenzoic acid (51) Methyl 2-(5-carbamoyl-1-(2-(5-carbamoyl-2-(4-cyano-2-(methoxycarbonyl)phenyl)-4-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)-4-methoxy-1H-benzo[d]imidazol-2-yl)-5-cyanobenzoate (52) or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof.

16. A compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, for use in a method of therapy.

17. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, and a pharmaceutically acceptable excipient.

18. A compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, or pharmaceutical composition according to claim 17 for use in the treatment or prevention of a disease ameliorated by the modulation of STING.

19. A method of treating or preventing a disease ameliorated by the modulation of STING, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, or pharmaceutical composition according to claim 17.

20. Use of a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and/or N-oxide thereof, in the preparation of a medicament for treating or preventing a disease ameliorated by the modulation of STING.

Description

EXAMPLES

[0392] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

Acronyms

[0393] For convenience, many chemical moieties are represented using well known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), isopropyl (iPr), n-butyl (nBu), tert-butyl (tBu), phenyl (Ph), benzyl (Bn), methoxy (MeO), ethoxy (EtO), trimethylsilyl (TMS), and acetyl (Ac).

[0394] For convenience, many chemical compounds are represented using well known abbreviations, including but not limited to, methanol (MeOH), deuterated methanol (MeOD-d.sub.4 or CD.sub.3OD) ethanol (EtOH), isopropanol (i-PrOH), ether or diethyl ether (Et.sub.2O), ethyl acetate (EtOAc), acetic acid (AcOH), acetonitrile (MeCN or ACN), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), deuterated chloroform (CDCl.sub.3), diethylamine (DEA), deuterated dimethylsulfoxide (DMSO-d.sub.6), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl), meta-chloroperoxybenzoic acid (mCPBA), 1,1′-bis(diphenylphosphino)ferrocene (dppf), tert-butyloxycarbonyl (Boc, BOC), 2-(trimethylsilyl)ethoxymethyl (SEM), triethylamine (Et.sub.3N or TEA), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA or DIEA), 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (II) (PdCl.sub.2(dppf)), trans-dichlorobis(triphenylphosphine)palladium(II) (PdCl.sub.2(PPh.sub.3).sub.2), tris(dibenzylideneacetone) dipalladium(0) (Pd.sub.2(dba).sub.3), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh.sub.3).sub.4), propylphosphonic anhydride (T3P), hexamethylphosphoramide (HMPA), 1,2-dichloroethane (DCE), chromium(VI) oxide (CrO.sub.3), n-bromosuccinimide (NBS), potassium hydroxide (KOH), benzoyl peroxide (BPO), carbon tetrachloride (CCl.sub.4), petroleum ether (Pet. Ether), potassium carbonate (K.sub.2CO.sub.3), sodium sulfate (Na.sub.2SO.sub.4), lithium diisopropylamine (LDA), azobisisobutyronitrile (AIBN), N-methylmorpholine N-oxide (NMO), benzoyl peroxide (BPO), 1,1′-carbonyldiimidazole (CDI) and 1-hydroxybenzotriazole (HOBt).

[0395] In addition, TLC refers to thin layer chromatography.

[0396] General Experimental Details

[0397] Unless otherwise stated the following generalisations apply. .sup.1H NMR spectra were recorded on a Bruker AVANCE III (400 MHz). The multiplicity of a signal is designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; tt, triplet of triplets; td, triplet of doublets; ddd, doublet of doublet of doublets; br, broad; m, multiplet. All observed coupling constants, J, are reported in Hertz. Exchangeable protons are not always observed.

[0398] LCMS data was generated using the conditions described below. Chlorine isotopes are reported as .sup.35Cl, Bromine isotopes are reported as either .sup.79Br or .sup.81Br or both .sup.79Br/.sup.61Br.

[0399] LC-MS Method A (LCMS-A):

[0400] Equipment Information

[0401] LC model: Agilent 1200

[0402] (Pump type: Binary Pump, Detector type: DAD)

[0403] MS model: Agilent G6110A Quadrupole

[0404] Parameters of LCMS

[0405] LC: Column: Xbridge-C18, 2.5 μm, 2.1×30 mm [0406] Column temperature: 30° C. [0407] Acquisition of wavelength: 214 nm, 254 nm [0408] Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH

[0409] MS: Ion source: ES+ (or ES−) MS range: 50˜900 m/z [0410] Fragmentor: 60 Drying gas flow: 10 L/min [0411] Nebulizer pressure: 35 psi Drying gas temperature: 350° C. [0412] Vcap: 3.5 kV

TABLE-US-00009 Gradient Table: Flow (mL/min) T (min) A (%) B (%) 0.5 0.0 70 30 0.5 0.2 70 30 0.5 1.8 5 95 0.5 2.4 5 95 0.5 2.6 70 30 0.5 3.5 70 30

[0413] Sample Preparation

[0414] The sample was dissolved in methanol, the concentration about 0.11˜1 mg/mL, then filtered through a 0.22 μm syringe filter. (Injection volume: 1˜10 μL)

[0415] LC-MS Method B (LCMS-B):

[0416] Equipment Information

[0417] LC model: Agilent 1200

[0418] (Pump type: Binary Pump, Detector type: DAD)

[0419] MS model: Agilent G6110A Quadrupole

[0420] Parameters of LCMS

[0421] LC: Column: Xbridge-C18, 2.5 μm, 2.1×30 mm [0422] Column temperature: 30° C. [0423] Acquisition of wavelength: 214 nm, 254 nm [0424] Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH

[0425] MS: Ion source: ES+ (or ES−) MS range: 50˜900 m/z [0426] Fragmentor: 60 Drying gas flow: 10 L/min [0427] Nebulizer pressure: 35 psi Drying gas temperature: 350° C. [0428] Vcap: 3.5 kV

TABLE-US-00010 Gradient Table: Flow (mL/min) T (min) A(%) B (%) 0.5 0.0 70 30 0.5 0.3 70 30 0.5 0.6 50 50 0.5 0.9 40 60 0.5 1.2 30 70 0.5 3.2 5 95 0.5 3.5 5 95 0.5 4.0 70 30 0.5 5.0 70 30

[0429] Sample Preparation

[0430] The sample was dissolved in methanol, the concentration about 0.11˜1 mg/mL, then filtered through a 0.22 μm syringe filter. (Injection volume: 1˜10 μL)

[0431] LC-MS Method C (LCMS-C):

[0432] Equipment Information

[0433] LC model: Waters 2695 alliance

[0434] (Pump type: Quaternary Pump, Detector: 2996 Photodiode Array Detector)

[0435] MS model: Micromass ZQ

[0436] Parameters of LCMS

[0437] LC: Column: Xbridge-C18, 3.5 μm, 2.1×50 mm [0438] Column temperature: 30° C. [0439] Acquisition of wavelength: 214 nm, 254 nm [0440] Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH

[0441] MS: Ion source: ES+ (or ES−) MS range: 50˜900 m/z [0442] Capillary: 3 kV Cone: 3 V Extractor: 3 V [0443] Drying gas flow: 600 L/hr Cone: 50 L/hr [0444] Desolvation temperature: 300° C. [0445] Source temperature: 100° C.

TABLE-US-00011 Gradient Table: Flow (mL/min) T (min) A (%) B (%) 0.3 0.0 80 20 0.3 0.5 80 20 0.3 0.8 50 50 0.3 1.2 35 65 0.3 2.0 20 80 0.3 4.0 5 95 0.3 5.0 5 95 0.3 5.8 15 85 0.3 6.2 80 20 0.3 8.0 80 20

[0446] Sample Preparation

[0447] The sample was dissolved in methanol, the concentration about 0.11˜1 mg/mL, then filtered through a 0.22 μm syringe filter. (Injection volume: 1˜10 μL)

[0448] Other Chromatography

[0449] Analytical thin-layer chromatography was performed on Merck silica gel 60 F254 aluminium-backed plates which were visualised using fluorescence quenching under UV light or a basic KMnO.sub.4 dip or Ninhydrin dip.

[0450] Preparative thin-layer chromatography (prep TLC) was performed using Tklst (China), grand grade: (HPTLC): 8±2 μm>80%; (TLC): 10-40 μm. Type: GF254. Compounds were visualised by UV (254 nm).

[0451] Column chromatography was performed using Tklst (China), grand grade, 100-200 meshes silica gel.

[0452] Where necessary, anhydrous solvents were purchased from Sigma-Aldrich or dried using conventional methods. Solutions of inorganic acids or bases were made up as aqueous solutions unless stated otherwise.

[0453] Solutions of hydrogen chloride, sodium hydroxide, potassium carbonate and sodium bicarbonate are aqueous, unless otherwise stated.

Intermediate Preparations

(i) 4,4′-(Ethane-1,2-diylbis(azanediyl))bis(3-aminobenzamide) (I4)

[0454] ##STR00026##

(a) tert-Butyl (2-((4-carbamoyl-2-nitrophenyl)amino)ethyl)carbamate (I1)

[0455] A suspension of 4-chloro-3-nitrobenzamide (8.0 g, 39.9 mmol), tert-butyl (2-aminoethyl)carbamate (6.40 g, 39.9 mmol) and Et.sub.3N (8.1 g, 79.8 mmol) in NMP (80 mL) was heated at 150° C. under N.sub.2 overnight. Water (500 mL) was added followed by Pet. Ether/EtOAc (5:1, 300 mL) and the resulting precipitate was collected by filtration to give the title compound (12.0 g, 92%) as a yellow solid. LCMS-B: rt 3.2 min, m/z 347.1 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.65 (s, 1H), 8.44 (t, J=5.8 Hz, 1H), 8.05-7.92 (m, 2H), 7.27 (s, 1H), 7.14 (d, J=9.1 Hz, 1H), 7.04 (t, J=5.8 Hz, 1H), 3.46-3.45 (m, 2H), 3.20-3.19 (m, 2H), 1.35 (s, 9H).

(b) 4-((2-Aminoethyl)amino)-3-nitrobenzamide hydrochloride (I2)

[0456] A mixture of tert-butyl (2-((4-carbamoyl-2-nitrophenyl)amino)ethyl)carbamate (I1) (12.0 g, 37.0 mmol) and a 5.5 M HCl in dioxane solution (200 mL) was stirred at room temperature overnight. The solvent was then removed under reduced pressure to give the title compound (8.0 g, 96%) as a yellow solid. LCMS-B: rt 1.2 min, m/z 225.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.65 (d, J=2.1 Hz, 1H), 8.42 (s, 1H), 8.25 (s, 2H), 8.05 (dd, J=9.0, 2.2 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 5.62 (br s, 3H), 3.76-3.74 (m, 2H), 3.01-2.97 (m, 2H).

[0457] A suspension of 4-((2-aminoethyl)amino)-3-nitrobenzamide hydrochloride (I2) (7.6 g, 33.9 mmol), 4-chloro-3-nitrobenzamide (6.80 g, 33.9 mmol) and Et.sub.3N (20.6 g, 203 mmol) in NMP (80 mL) was heated at 150° C. under N.sub.2 overnight. Additional 4-((2-aminoethyl)amino)-3-nitrobenzamide hydrochloride (12) (800 mg, 3.57 mmol) and Et.sub.3N (3.0 g, 29.6 mmol) were added and the mixture was heated at 150° C. under N.sub.2 overnight. The mixture was allowed to cool to room temperature, diluted with Pet. Ether/EtOAc (1:1, v/v, 500 mL) and the resulting precipitate was collected by filtration to give the title compound (12.0 g, 91%) as a yellow solid. LCMS-B: rt 1.3 min, m/z 389.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.62 (s, 4H), 7.99-7.95 (m, 4H), 7.30-7.28 (m, 4H), 3.70-3.64 (m, 4H).

(d) 4,4′-(Ethane-1,2-diylbis(azanediyl))bis(3-aminobenzamide) (I4)

[0458] A suspension of 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-nitrobenzamide) (I3) (12 g, 30.9 mmol), and 10% Pd/C (2.0 g) in DMF (200 mL) was heated at 100° C. under a H2 atmosphere overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (9.0 g, 90%) as a black solid. LCMS-B: rt 0.3 min, m/z 329.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.44 (s, 2H), 7.13 (d, J=8.2 Hz, 2H), 7.11 (s, 2H), 6.74 (s, 2H), 6.46 (d, J=8.0 Hz, 2H), 5.05 (s, 2H), 4.58 (s, 4H), 3.41-3.36 (m, 4H).

(ii) 4,4′-(Ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) I13

[0459] ##STR00027## ##STR00028##

(a) Methyl 4-fluoro-2-hydroxybenzoate (I5)

[0460] A mixture of 4-fluoro-2-hydroxybenzoic acid (50.0 g, 320.3 mmol) and concentrated H.sub.2SO.sub.4 (40 mL, 672.7 mmol) in MeOH (600 mL) was heated at reflux under N.sub.2 for 16 h. The mixture was poured into water (500 mL) and extracted with EtOAc (500 mL×3). The combined organic extracts were washed with water (500 mL×2), brine (500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 20:1) to give the title compound (50.0 g, 91%) as a white solid. LCMS-A (ES-API): rt 1.80 min, m/z 171.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.8 (s, 1H), 7.83 (dd, J=8.9, 6.8 Hz, 1H), 6.90-6.70 (m, 2H), 3.88 (s, 3H).

(b) Methyl 4-fluoro-2-hydroxy-3-nitrobenzoate (I6)

[0461] To a solution of methyl 4-fluoro-2-hydroxybenzoate I5 (50.0 g, 294.0 mmol) in concentrated H.sub.2SO.sub.4 (100 mL) at 0° C. under N.sub.2 was added concentrated HNO.sub.3 (20 mL, 382.1 mmol) dropwise and the mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was slowly poured into water (2.0 L) and extracted with EtOAc (1.5 L×3). The combined organic extracts were washed water (1.5 L×2), brine (1.5 L), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% Pet. Ether) to give a mixture of the title compound and an uncharacterised regioisomer (50 g, ˜3.75:1 uncharacterised regioisomer/title compound). The mixture was used in the next step without further purification or characterisation. LCMS-A (ES-API): rt 1.57 min (minor) m/z 216.0 [M+H]+ and rt 1.68 min (major) m/z 216.1 [M+H].sup.+.

[0462] A mixture of methyl 4-fluoro-2-hydroxy-3-nitrobenzoate (containing a major, uncharacterised regioisomer) I6 (50.0 g), CH.sub.3I (99.0 g, 697 mmol) and K.sub.2CO.sub.3 (64.1 g, 465 mml) in DMF (200 mL) was stirred at room temperature under N.sub.2 for 16 h. The mixture was poured into water (1.0 L), extracted with EtOAc (1.0 L×3) and the combined organic extracts were washed water (1.0 L×2), brine (1.0 L), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 40:1) and the fractions containing the minor component were collected to give the title compound (14.0 g, 21% over two steps) as a white solid. LCMS-C (ES-API): rt 3.53 min, m/z 230.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.12 (dd, J=9.1, 6.5 Hz, 1H), 7.50 (t, J=9.0 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H).

(d) Methyl 4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-methoxy-3-nitrobenzoate (I8)

[0463] A mixture of methyl 4-fluoro-2-methoxy-3-nitrobenzoate I7 (6.0 g, 26.2 mmol), tert-butyl (2-aminoethyl) carbamate (4.2 g, 26.2 mmol) and Et.sub.3N (5.3 g, 52.4 mmol) in NMP (100 mL) was heated at 80° C. under N.sub.2 for 16 h. The mixture was poured into water (500 mL), extracted with EtOAc (500 mL×3) and the combined organic extracts were washed with water (500 mL×2), brine (500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 10:1) to give the title compound (9.5 g, 98%) as a yellow solid. LCMS-C (ES-API): rt 4.43 min, m/z 392.1 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.79 (d, J=9.2 Hz, 1H), 6.96 (t, J=5.5 Hz, 1H), 6.74 (d, J=9.2 Hz, 1H), 6.70 (t, J=5.7 Hz, 1H), 3.79 (s, 6H), 3.27-3.21 (m, 2H), 3.11-3.06 (m, 2H), 1.37 (s, 9H).

(e) Methyl 4-((2-aminoethyl)amino)-2-methoxy-3-nitrobenzoate hydrochloride (I9)

[0464] A mixture of methyl 4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-methoxy-3-nitrobenzoate I8 (9.5 g, 25.7 mmol) and a 3 M HCl in dioxane solution (200 mL) was stirred at room temperature under N.sub.2 for 16 h. The mixture was concentrated under reduced pressure to give the title compound (6.0 g, 87%) as a white solid. LCMS-C (ES-API): rt 0.82 min, m/z 270.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.81 (dd, J=9.2, 3.8 Hz, 1H), 6.82-6.71 (m, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.31-3.28 (m, 4H).

(f) Dimethyl 4,4′-(ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzoate) (I10)

[0465] A mixture of methyl 4-((2-aminoethyl)amino)-2-methoxy-3-nitrobenzoate hydrochloride I9 (5.5 g, 18.0 mmol), methyl 4-fluoro-2-methoxy-3-nitrobenzoate 17 (4.68 g, 20.4 mmol) and Et.sub.3N (6.2 g, 61.3 mmol) in NMP (100 mL) was heated at 80° C. under N.sub.2 for 16 h. The mixture was poured into water (600 mL) and the resulting precipitate was collected by filtration to give the title compound (8.0 g, 82%) as a yellow solid. LCMS-C (ES-API): rt 4.75 min, m/z 477.1 [M−H].sup.−. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.76 (d, J=9.2 Hz, 2H), 6.77-6.74 (m, 4H), 3.78 (s, 6H), 3.77 (s, 6H), 3.40 (br s, 4H).

(g) 4,4′-(Ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzoic acid) (I11)

[0466] A mixture of dimethyl 4,4′-(ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzoate) I10 (4.0 g, 8.4 mmol) and NaOH (2.0 g, 50.2 mmol) in EtOH/water (50 mL/50 mL) was heated at 80° C. for 16 h. Most of the EtOH was removed under reduced pressure and the residue was diluted with water (50 mL) and acidified to pH 4-5 with a 2 M aqueous HCl solution. The resulting precipitate was collected by filtration to give the title compound (3.5 g, 93%) as a yellow solid. LCMS-C (ES-API): rt 3.45 min, m/z 473.1 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.6 (br s, 2H), 7.77 (d, J=9.1 Hz, 2H), 6.74 (d, J=9.3 Hz, 2H), 6.69 (t, J=5.5 Hz, 2H), 3.78 (s, 6H), 3.44 (br s, 4H).

(h) 4,4′-(Ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzamide) (I12)

[0467] A mixture of 4,4′-(ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzoic acid) I11 (3.4 g, 7.6 mmol), NH.sub.4Cl (2.4 g, 45.3 mmol), HOBt (3.1 g, 22.7 mmol), EDCl.HCl (4.3 g, 22.7 mmol) and DIPEA (5.9 g, 45.3 mmol) in DMF (300 mL) was stirred at room temperature under N.sub.2 for 16 h. The mixture was poured into water (600 mL) and the resulting precipitate was collected by filtration to give the title compound (2.4 g, 71%) as a yellow solid. LCMS-C (ES-API): rt 3.02 min, m/z 471.1 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.63 (d, J=9.0 Hz, 2H), 7.42 (br s, 4H), 6.77 (d, J=9.1 Hz, 2H), 6.60 (t, J=4.8 Hz, 2H), 3.77 (s, 6H), 3.39-3.36 (m, 4H).

(i) 4,4′-(Ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13)

[0468] A mixture of 4,4′-(ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzamide) I12 (1.0 g, 2.3 mmol) and 10% Pd/C (200 mg) in MeOH (150 mL) was stirred at room temperature under a H.sub.2 atmosphere (3 MPa) for 3 days. The mixture was filtered and the filtrate was concentrated under reduced pressure give the title compound (120 mg). The filter cake was washed with DMSO and the filtrate was freeze-dried to give additional title compound (680 mg). The isolated solids were combined to give the title compound (800 mg, 92%) as a brown solid. LCMS-B (ES-API): rt 1.09 min, m/z 388.8 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.39 (br s, 2H), 7.11 (d, J=8.4 Hz, 2H), 7.10 (br s, 2H), 6.37 (d, J=8.5 Hz, 2H), 5.23 (br s, 2H), 4.42 (br s, 4H), 3.66 (s, 6H), 3.35 (br s, 4H).

Examples

Example 1: 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid)

[0469] ##STR00029##

(a) Methyl 2-(bromomethyl)-5-chlorobenzoate (A1)

[0470] To a solution of methyl 5-chloro-2-methylbenzoate (5.0 g, 27.1 mmol) in 0014 (50 mL) was added NBS (5.3 g, 29.8 mmol) and AIBN (2.2 g, 13.5 mmol) and the mixture was heated at reflux under N.sub.2 for 4 h. The mixture was poured into water, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether) to give the title compound (3.0 g, 34%) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.85 (d, J=2.2 Hz, 1H), 7.69-7.62 (m, 2H), 4.99 (s, 2H), 3.88 (s, 3H).

(b) Methyl 5-chloro-2-formylbenzoate (A2)

[0471] To a solution of methyl 2-(bromomethyl)-5-chlorobenzoate A1 (480 mg, 1.83 mmol) in THF (7.0 mL) was added NMO (429 mg, 3.66 mmol) and the mixture was heated at 100° C. under N.sub.2 for 16 h. The mixture was poured into water (30 mL), extracted with EtOAc (30 mL×3) and the combined organic extracts were washed brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=1:0 to 250:1) to give the title compound (170 mg, 47%) as a white solid. LCMS-B (ES-API): rt 3.68 min, m/z 198.8 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.3 (s, 1H), 7.93-7.83 (m, 3H), 3.92 (s, 3H).

[0472] A mixture of methyl 5-chloro-2-formylbenzoate A2 (83 mg, 0.42 mmol), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) 113 (80 mg, 0.21 mmol) and NaHSO.sub.3 (44 mg, 0.42 mmol) in DMF (4 mL) was heated at 100° C. under N.sub.2 for 16 h. The mixture was diluted with water until a precipitate formed, which was collected by filtration to give the title compound (130 mg, 83%) as a brown solid. LCMS-B (ES-API): rt 3.95 min, m/z 745.4 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.80 (d, J=2.3 Hz, 2H), 7.71 (s, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.45 (s, 2H), 7.28 (dd, J=8.2, 2.3 Hz, 2H), 7.06 (d, J=8.6 Hz, 2H), 6.79 (d, J=8.2 Hz, 2H), 4.36 (s, 6H), 4.25 (s, 4H), 3.61 (s, 6H).

(d) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (1)

[0473] A mixture of dimethyl 6,6′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoate) A3 (120 mg, 0.16 mmol) and NaOH (39 mg, 0.96 mmol) in EtOH/H.sub.2O (5 mL/5 mL) was heated at 80° C. for 3 h. Most of the EtOH was removed under reduced pressure and the residue was adjusted to pH 4-5 with a 1 M aqueous HCl solution. The resulting precipitate was collected by filtration and purified by trituration with DCM/MeOH (10:1) to give the title compound (44 mg, 38%) as a brown solid. LCMS-B (ES-API): rt 2.66 min, m/z 717.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.80 (d, J=2.3 Hz, 2H), 7.71 (s, 2H), 7.64 (d, J=8.6 Hz, 2H), 7.44 (s, 2H), 7.14 (dd, J=8.4, 1.2 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 6.63 (d, J=8.2 Hz, 2H), 4.39 (s, 6H), 4.27 (s, 4H).

Example 2—2,2′-(Ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (2)

[0474] ##STR00030##

(a) Dimethyl 2,2′-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))dibenzoate (A4)

[0475] A solution of 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-aminobenzamide) 14 (500 mg 1.52 mmol), methyl 2-formylbenzoate (499 mg 3.04 mmol) and NaHSO.sub.3 (316 mg 3.04 mmol) in DMF (30 mL) was heated at 120° C. under N.sub.2 overnight. The resulting precipitate was collected by filtration, washed with water and DCM and dried under reduced pressure to give the title compound (100 mg, 26%) as a grey solid. LCMS-B (ES-API): rt 2.59 min; m/z 617.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.18 (d, J=1.0 Hz, 2H), 8.01 (br s, 2H), 7.89 (dd, J=7.9, 1.3 Hz, 2H), 7.65 (dd, J=8.5, 1.6 Hz, 2H), 7.54-7.43 (m, 2H), 7.28 (br s, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.21-7.16 (m, 2H), 6.52 (d, J=7.5 Hz, 2H), 4.26 (s, 4H), 3.53 (m, 6H).

(b) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (2)

[0476] A mixture of 2,2′-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))dibenzoate A4 (120 mg 0.19 mmol) and NaOH (47 mg 1.17 mmol) in EtOH/water (10 mL/2 mL) was heated at 50° C. under N.sub.2 overnight. The solvent was removed under reduced pressure and the residue was diluted with water (3 mL) and acidified to pH 4-5 with 1 M aqueous HCl solution. The resulting precipitate was collected by filtration, washed with water and dried at 60° C. to give the title compound (25 mg, 22%) as a black solid. LCMS-B (ES-API): rt 0.33 min; m/z 589.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.22 (s, 2H), 8.08 (br s, 2H), 7.91 (d, J=7.5 Hz, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.52 (t, J=7.4 Hz, 2H), 7.41 (br s, 2H), 7.36-7.28 (m, 2H), 7.21-7.28 (m, 2H), 6.74-6.59 (m, 2H), 4.42 (s, 4H).

Example 3—2,2′-(Ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl)bis(4-bromobenzoic acid) (3)

[0477] ##STR00031##

(a) Methyl 4-bromo-2-formylbenzoate (A5)

[0478] To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (2.0 g, 6.5 mmol) in acetonitrile (31 mL) at 0° C. was added NMO (50% aqueous solution, 4.6 g, 19.7 mmol) and the mixture was stirred at 0° C. overnight. The mixture was diluted with water, extracted with EtOAc and the organic layer was washed with a saturated aqueous NaHCO.sub.3 solution, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether/EtOAc=50:1) to give the title compound (622 mg, 39%) as a white solid. LCMS-B (ES-API): rt 3.93 min, m/z 242.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.4 (s, 1H), 8.01-7.95 (m, 2H), 7.85 (d, J=8.2 Hz, 1H), 3.90 (s, 3H).

(b) Dimethyl 2,2′-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(4-bromobenzoate) (A6)

[0479] To a solution of methyl 4-bromo-2-formylbenzoate A5 (200 mg, 0.82 mmol) and 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-aminobenzamide) 14 (135 mg, 0.41 mmol) in DMF (9 mL) was added NaHSO.sub.3 (85 mg, 0.82 mmol) and the mixture was heated at 120° C. under N.sub.2 overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (165 mg, 52%) as a yellow solid. LCMS-B (ES-API): rt 2.99 min, m/z 773.0/775.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.25 (s, 2H), 7.97 (br s, 2H), 7.82 (d, J=8.4 Hz, 2H), 7.76-7.73 (m, 4H), 7.32 (d, J=8.5 Hz, 2H), 7.27 (br s, 2H), 6.82 (s, 2H), 4.31 (s, 4H), 3.58 (s, 6H).

[0480] To a solution of dimethyl 2,2′-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(4-bromobenzoate) A6 (100 mg, 0.13 mmol) in EtOH (6 mL) was added a solution of NaOH (31 mg, 0.78 mmol) in water (4 mL) and the mixture was stirred at room temperature overnight. Most of the EtOH was removed under reduced pressure and the residue was diluted with water, acidified to pH 3-4 with a 2 M aqueous HCl solution and the resulting precipitate was collected by filtration and dried under reduced pressure to give the title compound (17 mg, 18%) as a yellow solid. LCMS-B (ES-API): rt 2.48 min, m/z 745.0/747.0 [M+H].sup.+. 1H NMR (400 MHz, DMSO-d.sub.6) δ 8.26 (s, 2H), 8.00 (br s, 2H), 7.83 (d, J=8.0 Hz, 2H), 7.75-7.65 (m, 4H), 7.37-7.21 (m, 4H), 6.79 (br s, 2H), 4.39 (s, 4H).

Example 4—2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (4)

[0481] ##STR00032##

(a) Dimethyl 2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))dibenzoate (A7)

[0482] A mixture of methyl 2-formylbenzoate (197 mg, 1.20 mmol), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) 113 and NaHSO.sub.3 (52 mg, 0.50 mmol) in DMF (20 mL) was heated at 120° C. under a N.sub.2 atmosphere overnight. The mixture was diluted with water and partitioned against EtOAc, resulting in formation of a precipitate. The precipitate was collected by filtration and triturated with DCM/MeOH=20/1 then dried under reduced pressure to give title compound (115 mg, 14%) as a white solid. LCMS-C (ES-API): rt 3.1 min, m/z 677.4 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.91 (d, J=7.9 Hz, 2H), 7.70 (br s, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.56-7.51 (m, 2H), 7.46 (br s, 2H), 7.34 (t, J=8.4 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 6.70 (d, J=7.2 Hz, 2H), 4.36 (s, 6H), 4.22 (s, 4H), 3.56 (s, 6H).

(b) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (4)

[0483] A mixture of dimethyl 2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))dibenzoate A7 (70 mg, 0.10 mmol) and NaOH (40.0 mg, 1.00 mmol) in MeOH/water (10 mL/1 mL) was stirred at room temperature overnight. Most of the MeOH was removed under reduced pressure and the residue was acidified to pH 5 with a 1 M aqueous HCl solution. The resulting precipitate was collected by filtration and dried under reduced pressure to give the title compound (16 mg, 25%) as a grey solid. LCMS-C (ES-API): rt 2.3 min, m/z 649.1 [M+H].sup.+. 1H NMR (400 MHz, DMSO-d.sub.6) δ 7.94 (d, J=7.9 Hz, 2H), 7.70 (br s, 2H), 7.56 (d, J=8.6 Hz, 2H), 7.51 (t, J=7.8 Hz, 2H), 7.45 (br s, 2H), 7.27 (t, J=7.5 Hz, 2H), 6.69 (d, J=8.7 Hz, 2H), 6.54 (d, J=7.6 Hz, 2H), 4.37 (s, 6H), 4.18 (s, 4H).

Example 5—2-(2-(1H-Tetrazol-5-yl)phenyl)-1-(2-(2-(2-(2H-tetrazol-5-yl)phenyl)-5-carbamoyl-1H-benzo[d]imidazol-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxamide (5)

[0484] ##STR00033##

(a) 2-(1H-Tetrazol-5-yl)benzaldehyde (A8)

[0485] To a solution of 5-phenyl-1H-tetrazole (5.0 g, 34.2 mmol) in THF (100 mL) at −78° C. under nitrogen was added s-butyllithium (1.3 M, 54.0 mL, 69.0 mmol) dropwise and the mixture was stirred at −78° C. for 30 min. DMF (20 mL, 300 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 10 min. The reaction was quenched with a 1 M aqueous HCl solution (100 mL) and the mixture was extracted with EtOAc (300 mL×3). The combined organic extracts were washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether/EtOAc=5:1-4:1) to give the title compound (4.0 g, 67%) as a white solid. LCMS-B (ES-API): rt 1.03 min; m/z 175.0 [M+H].sup.+.

(b) 2-(2-(1H-Tetrazol-5-yl)phenyl)-1-(2-(2-(2-(2H-tetrazol-5-yl)phenyl)-5-carbamoyl-1H-benzo[d]imidazol-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxamide (5)

[0486] A mixture of 2-(1H-tetrazol-5-yl)benzaldehyde A8 (500 mg, 2.88 mmol) 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-aminobenzamide) 14 (472 mg, 1.44 mmol) and NaHSO.sub.3 (299 mg, 2.88 mmol) in DMF (10 mL) was heated at 125° C. overnight. The mixture was poured into water (10 mL) and the resulting precipitate was collected by filtration, washed with water then triturated with MeOH to give the title compound (300 mg 17%) as a brown solid. LCMS-C (ES-API): rt 0.59 min; m/z 635.2 [M−H].sup.−. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (d, J=1.6 Hz, 2H), 7.97 (br s, 2H), 7.91 (d, J=7.8 Hz, 2H), 7.66 (dd, J=8.4, 1.7 Hz, 2H), 7.54 (t, J=7.6 Hz, 2H), 7.28 (br s, 2H), 7.14-7.12 (m, 4H), 6.63 (d, J=7.4 Hz, 2H), 4.20 (s, 4H).

Example 6—1,1′-(Ethane-1,2-diyl)bis(2-(2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (6)

[0487] ##STR00034##

[0488] A mixture of 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) 113 (50 mg, 0.13 mmol), 2-(2H-tetrazol-5-yl)benzaldehyde A8 (45 mg, 0.26 mmol) and NaHSO.sub.3 (40 mg, 0.39 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen overnight. The mixture was cooled to room temperature, poured into water (50 mL) and EtOAc (50 mL) was added. The resulting precipitate was collected by filtration and purified by prep-HPLC (Varian-940-LC; BOSTON, 10 μm, 250×2.12 mm column, eluting with a gradient of ACN in water with 0.1% HCO.sub.2H, at a flow rate of 15 mL/min) to give the title compound (4 mg, 4%) as a white solid. LCMS-C (ES-API): rt 2.36 min; m/z 697.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.95 (d, J=7.6 Hz, 2H), 7.69 (br s, 2H), 7.59-7.55 (m, 4H), 7.44 (br s, 2H), 7.25 (t, J=7.6 Hz, 2H), 6.76 (d, J=7.6 Hz, 2H), 6.69 (d, J=8.6 Hz, 2H), 4.28 (s, 6H), 4.08 (s, 4H).

Example 7—2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chlorobenzoic acid) (7)

[0489] ##STR00035##

(a) Methyl 2-(bromomethyl)-4-chlorobenzoate (A9)

[0490] To a solution of methyl 4-chloro-2-methylbenzoate (2.0 g, 10.8 mmol) in 0014 (40 mL) was added NBS (2.0 g, 11.9 mmol) and AIBN (1.0 g, 5.42 mmol) and the mixture was heated at 80° C. under N.sub.2 overnight. The mixture was poured into water, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1) to give the title compound (2.3 g, 82%) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.85 (d, J=2.2 Hz, 1H), 7.69-7.62 (m, 2H), 4.99 (s, 2H), 3.88 (s, 3H).

(b) Methyl 4-chloro-2-formylbenzoate (A10)

[0491] To a solution of methyl 2-(bromomethyl)-4-chlorobenzoate (A9) (2.3 g, 8.73 mmol) in THF (30 mL) was added NMO (2.0 g, 17.5 mmol) and the mixture was heated at reflux under N.sub.2 for 16 h. Additional NMO (1.0 g, 8.73 mmol) and THF (15 mL) were added and the mixture was heated at reflux under N.sub.2 for a further 4 h. The mixture was poured into water (40 mL), extracted with EtOAc (40 mL×3) and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=200:1 to 150:1 to 120:1) to give the title compound (380 mg, 22%) as a yellow solid. LCMS-B (ES-API): rt 3.71 min, m/z 199.0, 201.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.4 (s, 1H), 7.94-7.81 (m, 3H), 3.91 (s, 3H).

[0492] A mixture of methyl 4-chloro-2-formylbenzoate (A10) (0.100 g, 0.50 mmol), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (0.098 g, 0.25 mmol) and NaHSO.sub.3 (0.052 g, 0.50 mml) in DMF (4 mL) was heated at 100° C. under N.sub.2 for 16 h. The mixture was poured into water (10 mL), extracted with EtOAc (10 mL×3) and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with MeOH to give the title compound (66 mg, 35%) as a white solid. LCMS-B (ES-API): rt 3.15 min, m/z 745.2, 747.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.89 (d, J=8.5 Hz, 2H), 7.68-7.66 (m, 4H), 7.58 (dd, J=8.5, 2.1 Hz, 2H), 7.45 (d, J=1.9 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 6.80 (br s, 2H), 4.38 (s, 6H), 4.29 (s, 4H), 3.60 (s, 6H).

(d) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chlorobenzoic acid) (7)

[0493] A mixture of dimethyl 2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chlorobenzoate) (A11) (66 mg, 0.09 mmol) and NaOH (21 mg, 0.53 mmol) in EtOH/H.sub.2O (5 mL/5 mL) was stirred at room temperature overnight. The mixture was poured into water (10 mL) and washed with EtOAc (10 mL×3). The aqueous phase was adjusted to pH 4-5 with 1 M aqueous HCl and the resulting precipitate was collected by filtration and triturated with 10:1 DCM/MeOH to give the title compound (7.4 mg, 11%) as a white solid. LCMS-B (ES-API): rt 2.75 min, m/z 717.1, 719.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.2 (br s, 2H), 7.91 (d, J=8.5 Hz, 2H), 7.67 (d, J=2.0 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.52 (dd, J=8.5, 1.8 Hz, 2H), 7.43 (d, J=2.0 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 6.56 (br s, 2H), 4.41 (s, 6H), 4.27 (s, 4H).

Example 8—6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-dichlorobenzoic acid) (8)

[0494] ##STR00036##

(a) 4,5-Dichloro-2-(methoxycarbonyl)benzoic acid (A12)

[0495] A solution of 5,6-dichloroisobenzofuran-1,3-dione (5 g, 23 mmol) in methanol (50 mL) was heated to reflux for 5 h. The mixture was concentrated under reduced pressure to afford the title compound (5.7 g, 100%) as a white solid. LCMS-B (ES-API): rt 3.45 min; m/z 249.0/251.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.00 (s, 1H), 7.96 (s, 1H), 3.81 (s, 3H).

(b) 5,6-Dichloroisobenzofuran-1(3H)-one (A13)

[0496] To a solution of 4,5-dichloro-2-(methoxycarbonyl)benzoic acid (A12) (1.0 g, 4.0 mmol) and Et.sub.3N (1.1 mL, 8.0 mmol) in dry THF (20 mL) at 0° C. was added ClCO.sub.2Et (654 mg, 6.0 mmol) dropwise. The mixture was stirred for 40 min, then filtered. The filtrate was diluted with dry THF (10 mL) and water (0.36 mL) was added followed by NaBH.sub.4 (303 mg, 8.0 mmol) portion wise and the mixture was stirred until TLC analysis showed all the starting material was consumed. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (812 mg, 87%) as a white solid. LCMS-B (ES-API): rt 3.61 min, m/z 202.9, 205.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (s, 1H), 8.05 (s, 1H), 5.41 (s, 2H).

[0497] A mixture of 5,6-dichloroisobenzofuran-1(3H)-one (A13) (580 mg, 2.86 mmol), NBS (610 mg, 3.43 mmol) and AIBN (46.9 mg, 0.286 mmol) in benzene (20 mL) was heated at reflux under N.sub.2 overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 50:1) to give the title compound (545 mg, 68%) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.19 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H).

(d) 4,5-Dichloro-2-formylbenzoic acid (A15)

[0498] A mixture of 3-bromo-5,6-dichloroisobenzofuran-1(3H)-one (A14) (547 mg, 1.95 mmol) in water (10 mL) was heated at reflux for 90 min. The water was then removed by freeze drying to give the title compound (410 mg, 96%) as a white solid. LCMS-B (ES-API): rt 3.29 min, m/z 218.9, 220.9 [M+H].sup.+. 1H NMR (400 MHz, DMSO-d.sub.6) δ 11.1 (br s, 2H), 8.09 (s, 1H), 7.96 (s, 1H).

(e) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-dichlorobenzoic acid) (8)

[0499] A mixture of 4,5-dichloro-2-formylbenzoic acid (A15) (0.100 g, 0.459 mmol), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (0.089 g, 0.23 mmol) and NaHSO.sub.3 (0.119 g, 1.15 mmol) in DMF (3 mL) was heated at 80° C. under N.sub.2 overnight. The mixture was concentrated by freeze drying and the residue was purified by prep. HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, eluting with a gradient of ACN in water with 0.1% formic acid at a flow rate of 15.0 mL/min) to give the title compound (13.7 mg, 8%) as a white solid. LCMS-B (ES-API): rt 2.90 min, m/z 785.3, 787.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96 (s, 2H), 7.66 (s, 2H), 7.65 (d, J=8.6 Hz, 2H), 7.43 (br s, 2H), 6.94 (d, J=8.6 Hz, 2H), 6.88 (br s, 2H), 4.41 (s, 6H), 4.31 (s, 4H).

Example 9—1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (9)

[0500] ##STR00037##

(a) 5-chloro-2-(dimethoxymethyl)benzonitrile (A16)

[0501] To a solution of 5-chloro-2-formylbenzonitrile (2.0 g, 12.1 mmol) in MeOH (60 mL) was added trimethoxymethane (2.51 g, 24.2 mmol) and TsOH (0.21 g, 1.21 mmol) and the mixture was heated at 80° C. under N.sub.2 overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed with a saturated aqueous NaHCO.sub.3 solution, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 60:1) to give the title compound (1.7 g, 66%) as a yellow oil. LCMS-A (ES-API): rt 3.86 min, m/z 234.0, 236.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01 (d, J=2.2 Hz, 1H), 7.75 (dd, J=8.4, 2.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 5.50 (s, 1H), 3.26 (s, 6H).

(b) 5-(5-Chloro-2-(dimethoxymethyl)phenyl)-2H-tetrazole (A17)

[0502] To a solution of 5-chloro-2-(dimethoxymethyl)benzonitrile (A16) (1.0 g, 4.73 mmol) in NMP (20 mL) was added Et.sub.3N.HCl (1.95 g, 14.2 mmol) and NaN.sub.3 (1.54 g, 23.6 mmol) and the mixture was heated at 110° C. under N.sub.2 for 3 h. Most of the NMP was removed by lyophilisation and the residue was dissolved in DCM/MeOH (10:1) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH=50:1 to 10:1) to give the title compound (1.1 g, containing some NMP) as a yellow oil, which was used in the next step without further purification. LCMS-B (ES-API): rt 3.2 min, m/z 277.1, 279.1 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.85 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.62 (dd, J=8.4, 2.2 Hz, 1H), 6.07 (s, 1H), 3.22 (s, 6H).

[0503] A mixture of 5-(5-chloro-2-(dimethoxymethyl)phenyl)-2H-tetrazole (A17) (1.1 g) and 2 M aqueous H.sub.2SO.sub.4 (21.0 mL, 42.0 mmol) in acetone (30 mL) was stirred at room temperature for 3 h. The mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep. TLC (DCM/MeOH=5:1) to give the title compound (0.66 g, 67% over two steps) as a white solid. LCMS-B (ES-API): rt 2.83 min, m/z 209.0, 211.0 [M+H].sup.+. 1H NMR (400 MHz, DMSO-d.sub.6) δ 10.7 (s, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.58 (dd, J=8.4, 2.1 Hz, 1H).

(d) 1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (9)

[0504] To a solution of 4-chloro-2-(2H-tetrazol-5-yl)benzaldehyde (A18) (0.100 g, 0.481 mmol) in DMF (6 mL) was added 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (0.093 mg, 0.240 mmol) and NaHSO.sub.3 (0.050 mg, 0.481 mmol) and the mixture was heated at 80° C. under N.sub.2 overnight. The mixture concentrated under reduced pressure and the residue was purified by prep. HPLC (Varian-940-LC, YMC-C18, 5 μm, 150×20 mm column, eluting with a gradient of ACN in water with 0.1% formic acid, at a flow rate of 15 mL/min) to give the title compound (50 mg, 27%) as a white solid. LCMS-A (ES-API): rt 2.57 min, m/z 765.2, 767.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.95 (s, 2H), 7.73 (s, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.41 (s, 2H), 6.98 (d, J=7.7 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 6.56 (d, J=8.0 Hz, 2H), 4.38 (s, 6H), 3.88 (s, 4H).

Example 10—2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoic acid) (10)

[0505] ##STR00038##

(a) Ethyl 3-fluoro-2-methylbenzoate (A19)

[0506] To a solution of 3-fluoro-2-methylbenzoic acid (5.0 g, 32.5 mmol) in DMF (80 mL) was added K.sub.2CO.sub.3 (13.5 g, 97.5 mmol) and EtI (7.6 g, 48.8 mmol) and the mixture was stirred at room temperature under N.sub.2 for 3 h. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (5.4 g, 91%) as a yellow oil. LCMS-B (ES-API): rt 4.12 min, m/z 183.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.61 (d, J=7.2 Hz, 1H), 7.43-7.30 (m, 2H), 4.30 (q, J=7.1 Hz, 2H), 2.39 (d, J=2.3 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H).

(b) Ethyl 2-(bromomethyl)-3-fluorobenzoate (A20)

[0507] To a solution of ethyl 3-fluoro-2-methylbenzoate (A19) (5.4 g, 29.7 mmol) in CCl.sub.4 (100 mL) was added NBS (6.33 g, 35.6 mmol) and AIBN (2.43 g, 14.8 mmol) and the mixture was heated at 80° C. overnight. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (6.2 g, 86%) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.75-7.71 (m, 1H), 7.57-7.49 (m, 2H), 4.95 (d, J=1.7 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H).

[0508] To a solution of ethyl 2-(bromomethyl)-3-fluorobenzoate (A20) (6.2 g, 23.8 mmol) in THF (20 mL) was added NMO (11.2 g, 95.4 mmol) and the mixture was heated at reflux overnight. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 50:1) to give the title compound (3.6 g, 77%) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.3 (s, 1H), 7.79-7.72 (m, 1H), 7.69-7.57 (m, 2H), 4.34 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H).

(d) Diethyl2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoate) (A22)

[0509] To a solution of ethyl 3-fluoro-2-formylbenzoate (A21) (0.800 g, 4.49 mmol) in DMF (15 mL) was added 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide (I13) (0.872 g, 2.25 mmol) and NaHSO.sub.3 (0.930 g, 8.98 mmol) and the mixture was heated at 100° C. overnight. Additional ethyl 3-fluoro-2-formylbenzoate (A21) (0.100 g, 0.51 mmol) was added and the mixture was heated at 100° C. overnight. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The solid grey residue was rinsed with Pet. Ether/EtOAc=10:1 (50 mL×2) to give the title compound (1.1 g, 75%) as a grey solid. LCMS-B (ES-API): rt 3.12 min, m/z 741.4 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.84 (d, J=8.6 Hz, 2H), 7.80-7.60 (m, 6H), 7.56-7.36 (m, 6H), 4.80 (br s, 2H), 4.30 (s, 6H), 4.11 (br s, 2H), 3.99-3.85 (m, 4H), 0.77 (t, J=6.4 Hz, 6H).

(e) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoic acid) (10)

[0510] To a solution of diethyl 2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoate) (A22) (1.1 g, 1.49 mmol) in 5:1 EtOH/water (6 mL) was added NaOH (0.600 g, 14.9 mmol) and mixture was stirred at room temperature for 16 h. Most of the EtOH was removed under reduced pressure and the aqueous residue was adjusted to pH 5 with 1 M aqueous HCl. The resulting precipitate was collected by filtration and purified by prep. HPLC (Varian-940-LC, YMC-C18, 150×20 mm, 5 μm column, eluting with a gradient of ACN in water with 0.1% formic acid at a flow rate of 15.0 mL/min) to give the title compound (17 mg, 2%) as a white solid. LCMS-B (ES-API): rt 2.49 min, m/z 685.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.2 (s, 2H), 7.80-7.61 (m, 8H), 7.46 (s, 2H), 7.29-7.21 (m, 4H), 4.49 (br s, 2H), 4.31 (s, 6H), 4.17 (br s, 2H).

Example 11—2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chloro-3-fluorobenzoic acid) (11)

[0511] ##STR00039##

(a) 2-Amino-5-chloro-3-fluorobenzoic acid (A23)

[0512] A mixture of 2-amino-3-fluorobenzoic acid (5.0 g, 0.03 mol) and NCS (5.6 g, 0.04 mmol) in DMF (80 mL) was stirred at room temperature under N.sub.2 overnight. DCM (60 mL) was added and the mixture was washed with water (2×60 mL). During the second wash, a precipitate formed, which was collected by filtration and washed with water then dried under vacuum to give the title compound (4.0 g, 71%) as a brown solid. LCMS-B (ES-API): rt 3.3 min, m/z 189.9, 191.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.5) δ 7.51-7.50 (m, 1H), 7.44 (dd, J=11.2, 2.5 Hz, 1H).

(b) 2-Bromo-5-chloro-3-fluorobenzoic acid (A24)

[0513] To a solution of 2-amino-5-chloro-3-fluorobenzoic acid (A23) (4.0 g, 0.021 mol) in ACN (100 mL) at 0° C. was added 40% aqueous HBr (16.9 g, 0.083 mol) dropwise over 10 min. A solution of NaNO.sub.2 (1.6 g, 0.023 mol) in water (20 mL) was then added dropwise over 1 h and the mixture was stirred at 0° C. for 5 min. CuBr (3.6 g, 0.025 mol) was then added portion wise over 30 min and the mixture was heated at 70° C. for 1 h. Water (80 mL) was added and the resulting precipitate was collected by filtration and dried under vacuum to give the title compound (2.0 g, 41%) as a brown solid. LCMS-B (ES-API): rt 3.4 min, m/z 252.9, 254.8 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.0 (br s, 1H), 7.81 (dd, J=8.6, 2.4 Hz, 1H), 7.66 (dd, J=2.4, 1.4 Hz, 1H).

[0514] To a solution of 2-bromo-5-chloro-3-fluorobenzoic acid (A24) (2.0 g, 0.008 mol) in anhydrous THF (50 mL) at −30° C. was added i-PrMgCl (2 M solution in THF, 16.0 mL, 0.032 mol) dropwise and the mixture was stirred for 2 h. DMF (6 mL) was then added and the mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was removed under reduced pressure and the residue was diluted with 1 M aqueous HCl and extracted with EtOAc (30 mL×3). The combined organic extracts were washed with brine and concentrated under reduced pressure. The residue was purified by C.sub.18 reverse phase chromatography (Biotage) eluting with a gradient of water/MeOH to give the title compound (1.1 g, 69%) as a brown solid. .sup.1H NMR analysis showed the lactol form of the product. LCMS-B (ES-API): rt 2.90 min, m/z 202.9, 204.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (br s, 1H), 7.91 (dd, J=8.8, 1.5 Hz, 1H), 7.80 (d, J=1.5 Hz, 1H), 6.85 (br s, 1H).

(d) 2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chloro-3-fluorobenzoic acid) (11)

[0515] A mixture of 5-chloro-3-fluoro-2-formylbenzoic acid (A25) (0.800 g, 3.95 mmol), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (0.767 g, 1.97 mmol) and NaHSO.sub.3 (0.205 g, 1.97 mmol) in DMF (20 mL) was heated at 60° C. under N.sub.2 overnight. Water (30 mL) was added and the resulting precipitate was collected by filtration and purified by prep. HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, eluting with a gradient of ACN in water with 0.1% formic acid at a flow rate of 15.0 mL/min) to give the title compound (301 mg, 20%) as a grey solid. LCMS-B (ES-API): rt 2.75 min, m/z 753.3, 755.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.76-7.63 (m, 6H), 7.47 (s, 2H), 7.42-7.24 (m, 4H), 4.68-4.43 (m, 2H), 4.31 (s, 6H), 4.25-4.05 (m, 2H).

Example 12—2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl)bis(4-chloro-3-fluorobenzoic acid) (12)

[0516] ##STR00040##

(a) 4-Chloro-3-fluoro-2-formylbenzoic acid (A26)

[0517] To a solution of diisopropylamine (695 mg, 6.87 mmol) in THF (20 mL) at −78° C. under N.sub.2 was added n-BuLi (2.5 M in hexanes, 3.0 mL, 7.5 mmol) and the mixture was stirred at −78° C. for 1 h. 4-chloro-3-fluorobenzoic acid (1.0 g, 5.73 mmol) was then added and stirring was continued for a further 1 h. DMF (1.3 g, 17.2 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with a saturated aqueous NH.sub.4Cl solution and washed with EtOAc. The aqueous phase was concentrated under reduced pressure and the residue purified by silica gel chromatography (Pet. Ether to Pet. Ether/EtOAc=1:1 to DCM/MeOH=10:1) to give the title compound (1.0 g) as a white solid. LCMS analysis showed it was a ˜1:5 mixture of title compound/unreacted 4-chloro-3-fluorobenzoic acid, which was used directly in the next step without further purification. LCMS-B (ES-API): rt for title compound 2.99 min, m/z 203.0, 205.0 [M+H].sup.+.

(b) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chloro-3-fluorobenzoic acid) (12)

[0518] To a solution of a ˜1:5 mixture of 4-chloro-3-fluoro-2-formylbenzoic acid/4-chloro-3-fluorobenzoic acid (A26) (104 mg) and 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (100 mg, 0.26 mmol) in DMF (8 mL) was added NaHSO.sub.3 (107 mg, 1.03 mmol) and the mixture was heated at 120° C. under N.sub.2 overnight. The mixture was purified by prep. HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, eluting with a gradient of ACN in water with 0.1% formic acid at a flow rate of 15.0 mL/min) to give the title compound (5 mg) as a white solid. LCMS-B (ES-API): rt 2.66 min, m/z 753.1, 755.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.77 (d, J=8.6 Hz, 2H), 7.68 (d, J=3.0 Hz, 2H), 7.63-7.59 (m, 4H), 7.42 (br s, 2H), 7.03 (d, J=8.5 Hz, 2H), 4.50-4.47 (m, 2H), 4.37 (s, 6H), 4.24-4.21 (m, 2H).

Example 13—Dimethyl 6,6′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoate) (13) and 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoic acid) (14)

[0519] ##STR00041##

(a) Methyl 5-bromo-2-(bromomethyl)benzoate (A27)

[0520] A mixture of methyl 5-bromo-2-methylbenzoate (1.0 g, 4.4 mmol), NBS (0.56 g, 4.4 mmol) and AIBN (0.36 g, 2.2 mmol) in CCl.sub.4 (20 mL) was heated at 80° C. under N.sub.2 for 2 h. Additional NBS (56.3 mg, 0.44 mmol) was added and heating was continued at 80° C. for 1 h. Additional NBS (56.3 mg, 0.44 mmol) was added heating was continued at 80° C. for 1 h. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=120:1 to 80:1) to give the title compound (1.01 g, 75%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.98 (d, J=2.2 Hz, 1H), 7.80 (dd, J=8.3, 2.2 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 4.98 (s, 2H), 3.88 (s, 3H).

(b) Methyl 5-bromo-2-formylbenzoate (A28)

[0521] A solution of methyl 5-bromo-2-(bromomethyl)benzoate (A27) (1.01 g, 3.3 mmol) and NMO (1.55 g, 13.2 mmol) in THF (20 mL) was heated at reflux under N.sub.2 overnight. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 70:1) to give the title compound (217 mg, 26%) as a yellow solid. LCMS-B (ES-API): rt 3.7 min, m/z 243.0, 245.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.3 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 8.00 (dd, J=8.5, 2.2 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 3.91 (s, 3H).

[0522] A mixture of methyl 5-bromo-2-formylbenzoate (A28) (100 mg, 0.41 mmol), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (81.6 mg, 0.21 mmol) and NaHSO.sub.3 (21.9 mg, 0.21 mmol) in DMF (5 mL) was heated at 120° C. under N.sub.2 overnight. Water (20 mL) was added and resulting precipitate was collected by filtration and dried under vacuum to give the title compound (66 mg, 38%) as a black solid. LCMS-B (ES-API): rt 3.17 min, m/z 833.1, 835.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.94 (d, J=2.1 Hz, 2H), 7.72-7.69 (m, 4H), 7.46-7.41 (m, 4H), 7.11 (d, J=8.7 Hz, 2H), 6.77 (d, J=8.0 Hz, 2H), 4.36 (s, 6H), 4.25 (s, 4H), 3.61 (s, 6H).

(d) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoic acid) (14)

[0523] To a solution of dimethyl 6,6′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoate) (13) (60 mg, 0.07 mmol) in 9:1 EtOH/water (5.5 mL) was added NaOH (28 mg, 0.7 mmol) and the mixture was stirred at room temperature overnight. Most of the EtOH was removed under reduced pressure and the aqueous residue was adjusted to pH 5 with 2 M aqueous HCl. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (35 mg, 62%) as a black solid. LCMS-B (ES-API): rt 2.66 min, m/z 805.1, 807.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.95 (d, J=2.0 Hz, 2H), 7.72 (br s, 2H), 7.65 (d, J=8.6 Hz, 2H), 7.45 (br s, 2H), 7.33 (dd, J=8.0, 1.6 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 6.60 (d, J=8.2 Hz, 2H), 4.37 (s, 6H), 4.25 (s, 4H).

Example 15—6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-difluorobenzoic acid) (15)

[0524] ##STR00042##

(a) 4,5-Difluoro-2-formylbenzoic acid (A29)

[0525] To a solution of 2-bromo-4,5-difluorobenzoic acid (500 mg, 2.11 mmol) in THF (5 mL) at −78° C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 1.70 mL, 4.22 mmol) dropwise and the mixture was stirred at −78° C. for 45 min. DMF (0.20 mL, 2.53 mmol) was then added and stirring was continued at −78° C. for 2 h. The reaction was quenched with a saturated aqueous NH.sub.4C.sub.1 solution and the mixture was partitioned between EtOAc and water. The layers were separated and the aqueous phase was freeze dried. The residue was purified by prep. TLC (DCM/MeOH=10:1) to give the title compound (16 mg, 4%) as a white solid. LCMS-B (ES-API): rt 2.50 min; m/z 187.0 [M+H].sup.+.

(b) 6,6′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-difluorobenzoic acid) (15)

[0526] A mixture of 4,5-difluoro-2-formylbenzoic acid (A29) (16 mg, 0.086 mmol), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (23 mg, 0.07 mmol) and NaHSO.sub.3 (14 mg, 0.13 mml) in DMF (1 mL) was heated at 120° C. overnight. The mixture was partitioned between EtOAc and water, the layers were separated the aqueous layer was freeze dried. The residue was purified by prep. HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, eluting with a gradient of ACN in water with 0.1% formic acid at a flow rate of 15.0 mL/min) to give the title compound (10 mg, 32%) as a white solid. LCMS-B (ES-API): rt 2.54 min; m/z 721.2 [M+H].sup.+. 1H NMR (400 MHz, DMSO-d.sub.6) δ 7.81 (dd, J=8.3, 4.9 Hz, 2H), 7.68 (d, J=2.0 Hz, 2H), 7.60 (d, J=7.9 Hz, 2H), 7.49-7.38 (m, 4H), 7.08 (d, J=7.7 Hz, 2H), 4.48-4.46 (m, 2H), 4.34 (s, 6H), 4.23-4.22 (m, 2H).

Example 16—2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (16)

[0527] ##STR00043##

(a) 3,5-Difluoro-2-formylbenzoic acid (A30)

[0528] To a solution of 2-bromo-3,5-difluorobenzoic acid (500 mg, 2.11 mmol) in anhydrous THF (10 mL) at −30° C. was added i-PrMgCl (2 M solution in THF, 2.2 mL, 4.4 mmol) and the mixture was stirred at −30° C. for 3 h. DMF (1.5 mL) was added and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was concentrated under reduced pressure and the residue was diluted with 0.5 M aqueous HCl, extracted with DCM and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:0 to 100:1) to give the title compound (130 mg, 33%) as a yellow solid. .sup.1H NMR analysis showed the lactol form of the product. LCMS-B (ES-API): rt 2.69 min, m/z 186.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.44 (br s, 1H), 7.75 (td, J=9.3, 2.1 Hz, 1H), 7.62 (dd, J=7.0, 2.1 Hz, 1H), 6.82 (br s, 1H).

(b) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (16)

[0529] A mixture of 3,5-difluoro-2-formylbenzoic acid (A30) (130 mg, 0.70 mmol), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (136 mg, 0.35 mmol) and NaHSO.sub.3 (73 mg, 0.70 mmol) in DMF (8 mL) was heated at 120° C. under N.sub.2 for 16 h. The mixture was concentrated under reduced pressure until a precipitate formed, which was collected by filtration and purified by prep. HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, eluting with a gradient of ACN in water with 0.1% formic acid at a flow rate of 15.0 mL/min) to give the title compound (2.5 mg, 1%) as a white solid. LCMS-B (ES-API): rt 2.55 min, m/z 721.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.76-7.62 (m, 4H), 7.60-7.50 (m, 2H), 7.47 (d, J=2.8 Hz, 2H), 7.30-7.06 (m, 2H), 7.26 (d, J=8.6 Hz, 2H), 4.63-4.42 (m, 2H), 4.32 (s, 6H), 4.24-4.08 (m, 2H). .sup.1H NMR (400 MHz, 60° C., DMSO-d.sub.6) δ 7.75 (d, J=8.6 Hz, 2H), 7.66-7.51 (m, 4H), 7.38-7.16 (m, 4H), 7.20 (d, J=8.6 Hz, 2H), 4.43-4.24 (m, 10H).

Example 17—1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (17)

[0530] ##STR00044##

[0531] (a) Di-tert-butyl 2,2′-(2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chlorobenzoyl))bis(hydrazine-1-carboxylate) (A31) A mixture of 6,6′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (1) (0.300 g, 0.42 mmol), tert-butyl hydrazinecarboxylate (0.332 g, 2.52 mmol), EDCl.HCl (0.240 g, 1.26 mmol), HOBt (0.169 g, 1.26 mmol) and DIPEA (0.324 g, 2.52 mmol) in DMF (12 mL) was stirred at room temperature under N.sub.2 for 16 h. The mixture poured into water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic extracts were washed water (30×2 mL), brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (410 mg, >100%) as a yellow oil, which was used directly in the next step without further purification.

(b) 1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-(hydrazinecarbonyl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) dihydrochloride (A32)

[0532] A mixture of 2,2′-(2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chlorobenzoyl))bis(hydrazine-1-carboxylate) (A31) (410 mg, assumed quant. yield from previous step, 0.42 mmol) and a 3 M HCl in dioxane solution (6 mL) was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure to give the title compound (400 mg, >100%) as a grey solid, which was used directly in the next step without further purification. LCMS-B (ES-API): rt 1.67 min, m/z 745.3, 747.3 [M+H].sup.+.

(c) 1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (17)

[0533] A mixture of 1,1′-(ethane-1,2-diyl)bis(2-(4-chloro-2-(hydrazinecarbonyl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) dihydrochloride (A32) (90 mg, assumed quant. yield from previous step, 0.095 mmol), CDI (59 mg, 0.36 mmol) and Et.sub.3N (37 mg, 0.36 mmol) in DMF (4 mL) was heated at 40° C. under N.sub.2 for 16 h. The mixture poured into water (20 mL), extracted with EtOAc (15 mL×3) and the combined organic extracts were washed with water (15×2 mL), brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep. HPLC (Agilent, BOSTON, 250×2.12 mm, 10 μm column, eluting with a gradient of ACN in water with 0.1% formic at a flow rate of 20.0 mL/min) to give the title compound (5 mg, 7%) as a grey solid. LCMS-B (ES-API): rt 2.75 min, m/z 797.4, 799.4 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.6 (br s, 2H), 7.71 (br s, 2H), 7.66 (d, J=1.8 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.46 (br s, 2H), 7.05 (d, J=6.8 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 6.64 (d, J=8.3 Hz, 2H), 4.38 (s, 6H), 4.21 (s, 4H).

Example 18—2,2′-(Ethane-1,2-diylbis(5-carbamoyl-7-fluoro-4-methoxy-1H-benzo[d]imidazole-1,2-diyl)bis(3,5-difluorobenzoic acid) (18)

[0534] ##STR00045##

(a) 4,5-Difluoro-2-methoxybenzoic acid (A33)

[0535] Prepared from 2,4,5-trifluorobenzoic acid according to the procedure described in Bioorg. Med. Chem. Lett. 2016, 26, 2455. LCMS-B (ES-API): rt 2.98 min, m/z 189.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.99 (dd, J=10.5, 9.1 Hz, 1H), 6.90 (dd, J=11.2, 6.0 Hz, 1H), 4.05 (s, 3H).

(b) 4,5-Difluoro-2-methoxybenzamide (A34)

[0536] To a solution of 4,5-difluoro-2-methoxybenzoic acid (A33) (16.5 g, 85 mmol) in dry DCM (300 mL) at 0° C. was added DMF (10 drops) and (COCl).sub.2 (15 mL, 17 mmol) and the mixture was allowed to warm to room temperature and stirred for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in dry DCM (30 mL) and cooled to 0° C. Conc. aqueous NH.sub.4OH (26-28% aqueous solution, 70 mL) was added and the mixture was stirred at room temperature overnight. Most of the DCM was removed under reduced pressure and the resulting precipitate was collected by filtration and dried at 50° C. overnight to give the title compound (15.5 g, 97%) as a white solid. LCMS-B (ES-API): rt 2.76 min, m/z 188.0. [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.76 (dd, J=11.5, 9.6 Hz, 1H), 7.70 (br s, 1H), 7.66 (br s, 1H), 7.32 (dd, J=12.7, 6.5 Hz, 1H), 3.89 (s, 3H).

[0537] To a solution of 4,5-difluoro-2-methoxybenzamide (A34) (12.0 g, 64.2 mmol) in conc. H.sub.2SO.sub.4 (150 mL) was added a mixture of KNO.sub.3 (9.74 g, 96.3 mmol) in conc. H.sub.2SO.sub.4 (5 mL) dropwise over 30 min, maintaining the reaction temperature at 0° C. Following complete addition, TLC analysis showed the starting material was consumed. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=1:0 to 200:1 to 100:1) to give the title compound (4.5 g, 30%) as a white solid. LCMS-B (ES-API): rt 3.12 min, m/z 232.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.99 (br s, 1H), 7.96 (dd, J=10.4, 8.8 Hz, 1H), 7.92 (br s, 1H), 3.89 (s, 3H).

(d) 4,4′-(Ethane-1,2-diylbis(azanediyl))bis(5-fluoro-2-methoxy-3-nitrobenzamide) (A36)

[0538] To a solution of 4,5-difluoro-2-methoxy-3-nitrobenzamide (A35) (2.5 g, 10.8 mmol) in DMF (13 mL) was added K.sub.2CO.sub.3 (4.48 g, 32.4 mmol) and ethylenediamine (324 mg, 5.4 mmol) and the mixture was stirred at room temperature overnight. The mixture was carefully poured into ice water with stirring and the resulting precipitate was collected by filtration, washed with water (10 mL) and dried at 50° C. overnight to give the title compound (1.91 g, 73%) as a yellow solid. LCMS-B (ES-API): rt 3.07 min, m/z 485.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.56 (br s, 2H), 7.54 (br s, 2H), 7.47 (d, J=13.9 Hz, 2H), 6.27-6.20 (m, 2H), 3.75 (s, 6H), 3.34-3.33 (m, 4H).

(e) 2,2′-(Ethane-1,2-diylbis(5-carbamoyl-7-fluoro-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (18)

[0539] To a solution of 4,4′-(ethane-1,2-diylbis(azanediyl))bis(5-fluoro-2-methoxy-3-nitrobenzamide) (A36) (0.200 g, 0.41 mmol) in 1:1 DMSO/MeOH (8 mL) was added 3,5-difluoro-2-formylbenzoic acid (A30) (0.152 g, 0.82 mmol) and Na.sub.2S.sub.2O.sub.4 (0.214 g, 1.23 mmol). The flask was fitted with a condenser and the mixture was heated at 120° C. for 6 h. The mixture was concentrated under reduced pressure to remove most of the solvent, and the residue was diluted with water (20 mL) and adjusted to pH 5 with 1 M aqueous HCl. The resulting precipitate was collected by filtration, dried under vacuum at 50° C. overnight then purified by prep. HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, eluting with a gradient of ACN in water with 0.1% TFA at a flow rate of 15.0 mL/min) to give the title compound (20.7 mg, 7%) as a white solid. LCMS-B (ES-API): rt 2.71 min, m/z 757.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.78 (s, 2H), 7.71-7.61 (m, 4H), 7.40-7.30 (m, 2H), 7.15 (br s, 2H), 4.50-4.36 (m, 4H), 4.24 (s, 6H).

Example 19—1,1′-(Ethane-1,2-diyl)bis(2-(5-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (42)

[0540] ##STR00046##

(a) 4-Chloro-2-(dibromomethyl)benzonitrile (A37)

[0541] A solution of 4-chloro-2-methylbenzonitrile (10.0 g, 66.0 mmol), NBS (35.2 g, 198 mmol) and BPO (1.60 g, 6.60 mmol) in 0014 (200 mL) was heated at reflux under N.sub.2 for 24 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. ether/EtOAc=500:1 to 200:1) to give the title compound (13.0 g, 64%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (d, J=8.4 Hz, 1H), 7.91 (d, J=2.2 Hz, 1H), 7.70 (dd, J=8.3, 2.1 Hz, 1H), 7.40 (s, 1H).

(b) 4-Chloro-2-formylbenzonitrile (A38)

[0542] To a solution of 4-chloro-2-(dibromomethyl)benzonitrile A37 (10.0 g, 32.3 mmol) in acetonitrile (75 mL) was added a solution of AgNO.sub.3 (16.5 g, 97.0 mmol) in water (17 mL) and the mixture was heated at reflux for 20 min then allowed to cool to room temperature. The precipitate was removed by filtration and washed with DCM (3×200 mL). The combined filtrates were washed with water (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether/EtOAc=100:1 to 20:1) to give the title compound (5.30 g, 99%) as a yellow solid. LCMS-B (ES-API): rt 3.35 min, m/z 166.0, 168.0 [M+H].sup.+.

[0543] To a solution of 4-chloro-2-formylbenzonitrile A38 (5.00 g, 30.2 mmol) in MeOH (150 mL) was added trimethoxymethane (6.41 g, 60.4 mmol) and TsOH (520 mg, 3.02 mmol) and the mixture was heated at reflux for 16 h. The mixture was concentrated under reduced pressure and the residue was diluted with a saturated aqueous NaHCO.sub.3 solution and extracted with EtOAc. The organic extract was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether/EtOAc=100:1 to 70:1) to give the title compound (5.30 g, 83%) as a yellow oil. LCMS-B (ES-API): rt 3.83 min, m/z 212.1, 214.1 [M+H].sup.+.

(d) 5-(4-Chloro-2-(dimethoxymethyl)phenyl)-2H-tetrazole (A40)

[0544] A mixture of 4-chloro-2-(dimethoxymethyl)benzonitrile (3.00 g, 14.2 mmol), Et.sub.3N HCl (2.73 g, 19.9 mmol) and NaN.sub.3 (2.76 g, 42.5 mmol) in DMF (40 mL) was heated at 110° C. under N.sub.2 for 16 h. The mixture was poured into water (200 mL) and washed with EtOAc (100 mL×3). The aqueous layer was lyophilized to dryness and the residue was purified by silica gel chromatography (DCM/MeOH=100:1 to 20:1) to give the title compound (2.20 g, 61%) as a yellow oil. LCMS-B (ES-API): rt 3.27 min, m/z 253.0, 255.0 [M−H].sup.−.

(e) 5-Chloro-2-(2H-tetrazol-5-yl)benzaldehyde (A41)

[0545] To a solution of 5-(4-chloro-2-(dimethoxymethyl)phenyl)-2H-tetrazole A40 (900 mg, 3.53 mmol) in acetone (36 mL) was added a 2 M aqueous H.sub.2SO.sub.4 solution (36 mL, 70.6 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (365 mg, 50%) as a white solid. LCMS-B (ES-API): rt 2.94 min, m/z 209.0, 211.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.3 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.97-7.96 (m, 2H).

(f) 1,1′-(Ethane-1,2-diyl)bis(2-(5-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (42)

[0546] A solution of 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) I13 (200 mg, 0.51 mmol), 5-chloro-2-(2H-tetrazol-5-yl)benzaldehyde A41 (236 mg, 0.58 mmol) and Oxone® (380 mg, 0.61 mmol) in DMF (6 mL) was stirred at room temperature under N.sub.2 for 2 h. The mixture was poured into water (30 mL) and the resulting precipitate was collected by filtration and recrystallized from methanol to give the title compound (55 mg, 14%) as a grey solid. LCMS-B (ES-API): rt 2.76 min, m/z 765.0, 767.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.91 (d, J=8.4 Hz, 2H), 7.67-7.65 (m, 4H), 7.61 (d, J=8.1 Hz, 2H), 7.45 (br s, 2H), 6.93-6.91 (m, 4H), 4.29 (s, 6H), 4.17 (s, 4H).

Example 20—1,1′-(Ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (43)

[0547] ##STR00047## ##STR00048##

(a) 2-Bromo-3,5-difluorobenzonitrile (A42)

[0548] To a solution of 3,5-difluorobenzonitrile (5.00 g, 35.9 mmol), 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (10.3 g, 36.0 mmol) and ACN (5.90 g, 143.8 mmol) in DCM (75 mL) at 0° C. was added conc. H.sub.2SO.sub.4 (14.1 g, 143.8 mmol) dropwise over 30 min. The mixture was allowed to warm to room temperature then heated at 50° C. for 4 h. The mixture was partitioned between a 1 M aqueous sodium sulfite solution (120 mL) and DCM (70 mL), the layers were separated and the organic phase washed with a 1 M aqueous sodium sulfite solution (120 mL), water (70 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether/EtOAc=200:1 to 100:1) to give the title compound (7.2 g, 92%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.98-7.94 (m, 1H), 7.92 (dd, J=8.9, 2.8 Hz, 1H).

(b) 3,5-Difluoro-2-vinylbenzonitrile (A43)

[0549] To a solution of 2-bromo-3,5-difluorobenzonitrile A42 (5.00 g, 22.9 mmol) and tributyl(vinyl)stannane (21.8 g, 68.8 mmol) in toluene (100 mL) was added Pd(PPh.sub.3).sub.4 (2.65 g, 2.29 mmol) and the mixture was heated at reflux under N.sub.2 for 16 h. The mixture was poured into water (400 mL), extracted with EtOAc (200 mL×3) and the combined organic extracts were washed with water (100×2 mL), brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether/EtOAc=500:1 to 200:1) to give the title compound (2.00 g, 54%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.86-7.72 (m, 2H), 6.77 (dd, J=17.8, 11.8 Hz, 1H), 6.05 (d, J=17.8 Hz, 1H), 5.82 (d, J=11.7 Hz, 1H).

[0550] A solution of 3,5-difluoro-2-vinylbenzonitrile A43 (2.00 g, 12.1 mmol), Et.sub.3N.HCl (2.34 g, 18.8 mmol) and NaN.sub.3 (2.36 g, 36.3 mmol) in DMF (40 mL) was heated at 110° C. under N.sub.2 for 16 h. The mixture was poured into water (400 mL) and washed with EtOAc (250 mL×3). The aqueous phase was lyophilized to dryness and the residue was purified by silica gel chromatography (DCM/MeOH=100:1 to 20:1) to give the title compound (500 mg, 20%) as a brown solid. LCMS-B (ES-API): rt 3.23 min, m/z 209.0 [M+H].sup.+.

(d) 2,4-Difluoro-6-(1H-tetrazol-5-yl)benzaldehyde (A45)

[0551] A solution of 5-(3,5-difluoro-2-vinylphenyl)-1H-tetrazole A44 (500 mg, 2.40 mmol) in DCM/MeOH (6 mL/6 mL) was cooled to −70° C. and bubbled with O.sub.3 gas until a blue color persisted. Dimethyl sulfide (746 mg, 12.0 mmol) was then added and the mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH=100:1 to 50:1) to give the title compound (360 mg, 71%) as a yellow solid. LCMS-B (ES-API): rt 2.34 min, m/z 211.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.1 (s, 1H), 7.78-7.70 (m, 1H), 7.67 (d, J=8.9 Hz, 1H).

(e) 1,1′-(Ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (43)

[0552] A solution of 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) 113 (160 mg, 0.41 mmol), 2,4-difluoro-6-(1H-tetrazol-5-yl)benzaldehyde A45 (190 mg, 0.90 mmol) and Oxone® (304 mg, 0.49 mmol) in DMF (8 mL) was stirred at room temperature under N.sub.2 for 1 h. The mixture was poured into water (50 mL) and the resulting precipitate collected by filtration. Purification by prep-HPLC (Agilent, BOSTON 250×2.12 mm, 10 μm column, eluting with a gradient of ACN in water with 0.1% HCO.sub.2H at a flow rate of 20.0 mL/min) gave the title compound (5 mg, 2%) as a grey solid. LCMS-B (ES-API): rt 2.57 min, m/z 769.4 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.73-7.66 (m, 4H), 7.59 (d, J=8.4 Hz, 2H), 7.48-7.40 (m, 4H), 7.06-6.97 (m, 2H), 4.75-4.63 (m, 2H), 4.36-4.23 (m, 2H), 4.16 (s, 6H).

Example 21—1,1″-(Ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (44)

[0553] ##STR00049## ##STR00050##

(a) Di-tert-butyl 2,2′-(2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoyl))bis(hydrazine-1-carboxylate) (A46)

[0554] To a solution of 2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) 16 (500 mg, 0.7 mmol) in THF (2.5 mL) was added T3P® (50% w/w in EtOAc, 2.23 g, 3.5 mmol), tert-butyl carbazate (370 mg, 2.8 mmol) and Et.sub.3N (1.4 g, 14.0 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and LCMS analysis showed incomplete reaction. The residue was dissolved in THF (2.5 mL) and T3P® (50% w/w in EtOAc, 2.23 g, 3.5 mmol), tert-butyl carbazate (370 mg, 2.8 mmol) and Et.sub.3N (1.4 g, 14.0 mmol) were added and the mixture was heated at 80° C. for 7 h. The solvent was removed under reduced pressure and LCMS analysis showed incomplete reaction. The residue was dissolved in THF (2.5 mL) and T3P® (50% w/w in EtOAc, 2.23 g, 3.5 mmol), tert-butyl carbazate (370 mg, 2.8 mmol) and Et.sub.3N (1.4 g, 14.0 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and LCMS analysis showed incomplete reaction. The residue was dissolved in THF (2.5 mL) and T3P® (50% w/w in EtOAc, 2.23 g, 3.5 mmol), tert-butyl carbazate (370 mg, 2.8 mmol) and Et.sub.3N (1.4 g, 14.0 mmol) were added and the mixture was heated at 50° C. for 4 h. The solvent was removed under pressure and the residue was washed with diethyl ether (×3) to give the title compound (290 mg, 44%) as a light brown solid. LCMS-C (ES-API): rt 3.61 min; m/z 949.4 [M+H].sup.+.

(b) 1,1′-(Ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(hydrazinecarbonyl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) hydrochloride (A47)

[0555] To a solution of di-tert-butyl 2,2′-(2,2′-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo [d]imidazole-1,2-diyl))bis(3,5-difluorobenzoyl))bis(hydrazine-1-carboxylate) A46 (290 mg, 0.3 mmol) in dioxane (1 mL) was added a 4 M solution of HCl in dioxane (20 mL) dropwise and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the residue was washed with diethyl ether, petroleum ether and DCM to give the title compound (290 mg) as a yellow solid, which was used directly in the next step without further purification. LCMS-C (ES-API): rt 2.22 min; m/z 749.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.3 (s, 2H), 10.4 (s, 2H), 7.77-7.74 (m, 6H), 7.39-7.34 (m, 8H), 5.00-4.00 (m, 10H).

(c) 1,1′-(Ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (44)

[0556] To a solution of 1,1′-(ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(hydrazinecarbonyl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) hydrochloride A47 (100 mg, assumed 0.10 mmol) in DMF (1 mL) was added CDI (64.9 mg, 0.40 mmol) and Et.sub.3N (40.5 mg, 0.40 mmol) and the mixture was heated at 40° C. overnight. The mixture was concentrated under reduced pressure and the residue purified by prep. HPLC (Agilent YMC-C18, 5 μm, 250×20 mm column, eluting with a gradient of ACN in water with 0.1% Formic acid, at a flow rate of 15.0 mL/min) to give the title compound (2.5 mg, 3%) as a white solid. LCMS-B (ES-API): rt 4.08 min, m/z 801.0 [M+H].sup.+. .sup.1H NMR (400 MHz, room temperature, DMSO-d.sub.6) δ 12.7 (br s, 2H), 7.81-7.73 (m, 3H), 7.69-7.51 (m, 6H), 7.17 (d, J=8.4 Hz, 2H), 6.85 (s, 1H), 4.56 (d, J=9.6 Hz, 2H), 4.39 (s, 6H), 4.18 (d, J=9.6 Hz, 2H). .sup.1H NMR (400 MHz, 60° C., DMSO-d.sub.6) δ 12.6 (s, 2H), 7.66-7.56 (m, 7H), 7.34 (s, 2H), 7.13 (d, J=8.8 Hz, 2H), 6.87 (s, 1H), 4.50 (s, 2H), 4.35 (s, 6H), 4.18 (s, 2H).

Example 22: 1,1-(Ethane-1,2-diyl)bis(2-(2-bromo-4-chloro-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (45) and 1,1′-(ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (46)

[0557] ##STR00051## ##STR00052##

(a) 2-Bromo-4-chloro-6-fluorobenzaldehyde (A48)

[0558] To a solution of 1,2-dibromo-5-chloro-3-fluorobenzene (2.0 g, 6.94 mmol) in dry THF (10 mL) at −65° C. under N.sub.2 was added i-PrMgCl (2 M solution in THF, 3.81 mL, 7.63 mmol) dropwise at such a rate that the temperature of the mixture did not exceed −50° C. The mixture was then cooled to −72° C. and stirred for 1 h. DMF (2.54 g, 34.6 mmol) was then added dropwise at such a rate that the temperature of the mixture did not exceed −55° C. and stirring was continued at −70° C. for 15 minutes. The mixture was quenched by dropwise addition of water (5 mL) and then extracted with EtOAc (50 mL×2). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure and the residue was purified by silica gel chromatography (Petroleum Ether) to give the title compound (800 mg, 50%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.20 (d, J=1.2 Hz, 1H), 7.45 (t, J=1.7 Hz, 1H), 7.13 (dd, J=10.0, 2.0 Hz, 1H).

(b) 1,1′-(Ethane-1,2-diyl)bis(2-(2-bromo-4-chloro-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (45)

[0559] A mixture of 2-bromo-4-chloro-6-fluorobenzaldehyde (A48) (1.34 g, 5.67 mmol), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (1.0 g, 2.57 mmol) and NaHSO.sub.3 (670 mg, 6.44 mmol) in DMF (16.8 mL) was heated at 80° C. overnight. The mixture was allowed to cool to room temperature, poured into water and the resulting precipitate collected by filtration. The collected solid was recrystallized from formic acid to give the title compound (700 mg, 33%) as a brown solid. LCMS-B (ES-API): rt 3.28 min, m/z 820.9, 822.9 [M+H].sup.+.

[0560] A mixture of 1,1′-(ethane-1,2-diyl)bis(2-(2-bromo-4-chloro-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (45) (700 mg, 0.85 mmol) and CuCN (228 mg, 2.55 mmol) in NMP (3.5 mL) was heated at 170° C. for 4 h. The mixture was allowed to cool to room temperature, poured into water and the resulting precipitate collected by filtration. The collected solid was purified by silica gel chromatography (DCM/MeOH, 100:1 to 10:1) to give the title compound (330 mg, 54%) as a brown solid. LCMS-C (ES-API): rt 3.49 min, m/z 715.06 [M+H].sup.+.

(d) 1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (46)

[0561] A mixture of 1,1′-(ethane-1,2-diyl)bis(2-(4-chloro-2-cyano-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (A49) (130 mg, 0.182 mmol), Et.sub.3N.HCl (150 mg, 1.09 mmol) and NaN.sub.3 (141.7 mg, 2.18 mmol) in DMF (2.4 mL) was heated at 80° C. under N.sub.2 overnight. The mixture was returned to room temperature and poured into water. No precipitate formed so the mixture was concentrated under reduced pressure at 55° C. and the residue purified by silica gel chromatography (DCM/MeOH, 5:1 containing 2.5% v/v conc. aq. NH.sub.4OH) followed by prep-HPLC (Agilent, YMC-C18, 150×20 mm, 5.0 μm column, eluting with a gradient of MeOH in water with 0.1% TFA at a flow rate of 15.0 mL/min) to give the title compound (14.7 mg, 11%) as a white solid. LCMS-B (ES-API): rt 2.68 min, m/z 801.2, 803.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96-7.63 (m, 6H), 7.58-7.33 (m, 4H), 7.24-7.09 (m, 2H), 4.84-4.55 (m, 2H), 4.43-4.25 (m, 2H), 4.14 (s, 6H).

Example 23: 2-(5-Carbamoyl-1-(2-(5-carbamoyl-2-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)-4-methoxy-1H-benzo[d]imidazol-2-yl)-5-chloro-3-fluorobenzoic acid (47)

[0562] ##STR00053##

[0563] A mixture of 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (100 mg, 0.26 mmol), 4-chloro-2-(2H-tetrazol-5-yl)benzaldehyde (A18) (54 mg, 0.26 mmol), 5-chloro-3-fluoro-2-formylbenzoic acid (A25) (52 mg, 0.26 mmol) and NaHSO.sub.3 (80 mg, 0.78 mmol) in DMF (8.0 mL) was heated at 120° C. under a N.sub.2 atmosphere for 16 h. The mixture was cooled to room temperature, poured into water (40 mL) and the resulting precipitate collected by filtration. Purification by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.3 mm column, eluting with a gradient of ACN in water with 0.1% formic acid, at a flow rate of 20 mL/min) gave the title compound (8.0 mg, 4%) as a white solid. LCMS-B (ES-API): rt 2.630 min, m/z 759.1, 761.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.97 (d, J=1.6 Hz, 1H), 7.74-7.62 (m, 5H), 7.51-7.42 (m, 2H), 7.23-6.96 (m, 4H), 6.71-6.61 (m, 1H), 4.41-4.25 (m, 2H), 4.37 (s, 3H), 4.27 (s, 3H), 4.22-4.11 (m, 2H).

Example 24: 1,1-(Ethane-1,2-diyl)bis(2-(2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (48)

[0564] ##STR00054##

(a) 2-(Bromomethyl)-3-fluorobenzonitrile (A50)

[0565] To a solution of 3-fluoro-2-methylbenzonitrile (4.4 g, 32.6 mmol) in CCl.sub.4 (45 mL) was added NBS (29.0 g, 163 mmol) and BPO (0.8 g, 3.3 mmol) and the mixture was heated at reflux overnight. The mixture was returned to room temperature and the solids were removed by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography (Pet. Ether/EtOAc=200:1 to 50:1) to give the title compound (5.2 g, 74%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.82 (dd, J=7.6, 0.8 Hz, 1H), 7.70-7.60 (m, 2H), 4.74 (d, J=0.8 Hz, 2H).

(b) 3-Fluoro-2-formylbenzonitrile (A51)

[0566] To a solution of 2-(bromomethyl)-3-fluorobenzonitrile (A50) (1.0 g, 4.8 mmol) in acetonitrile (20 mL) was added NMO (2.3 g, 19.2 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was poured into water, extracted with EtOAc and the organic extract dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (540 mg, 75%) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.3 (s, 1H), 7.94-7.85 (m, 2H), 7.85-7.77 (m, 1H).

[0567] To a solution of 3-fluoro-2-formylbenzonitrile (A51) (500 mg, 3.35 mmol) in DMF (5.0 mL) was added 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (592 mg, 1.52 mmol) and NaHSO.sub.3 (397 mg, 3.81 mmol) and the mixture was heated at 80° C. overnight. The mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography (DCM/MeOH=150:1 to 30:1) to give the title compound (76 mg, 8%) as a brown solid. LCMS-A (ES-API): rt 2.8 min, m/z 647.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.70 (br s, 2H), 7.66-7.64 (m, 4H), 7.55 (br s, 2H), 7.44-7.41 (m, 4H), 7.07 (d, J=8.7 Hz, 2H), 4.65 (s, 4H), 4.42 (s, 6H).

(d) 1,1′-(Ethane-1,2-diyl)bis(2-(2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (48)

[0568] To a solution of 1,1′-(ethane-1,2-diyl)bis(2-(2-cyano-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (A52) (76 mg, 118 mmol) in DMF (0.5 mL) was added Et.sub.3N.HCl (97 mg, 0.705 mmol) and NaN.sub.3 (92 mg, 1.42 mmol) and the mixture was heated at 80° C. overnight. The mixture was concentrated under reduced pressure and the residue purified by prep-HPLC (Agilent YMC-C18, 5 μm, 150×20 mm column, eluting with a gradient of ACN in water with 0.1% formic acid, at a flow rate of 15.0 mL/min) to give the title compound (4.6 mg, 5%) as a brown solid. LCMS-B (ES-API): rt 2.445 min; m/z 733.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (d, J=7.8 Hz, 1H), 7.83 (d, J=7.9 Hz, 2H), 7.70-7.58 (m, 4H), 7.56-7.37 (m, 4H), 6.96 (d, J=8.2 Hz, 2H), 6.49 (d, J=8.4 Hz, 1H), 4.40-4.25 (m, 2H), 4.19 (s, 6H), 4.09-3.99 (m, 2H).

Example 25: 1,1-(Ethane-1,2-diyl)bis(2-(2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (49)

[0569] ##STR00055##

(a) Methyl 2-bromo-3-fluorobenzoate (A53)

[0570] To a solution of 2-bromo-3-fluorobenzoic acid (5.00 g, 22.9 mmol) in MeOH (40 mL) was added conc. H.sub.2SO.sub.4 (3.0 mL) and the mixture was heated at reflux overnight. The mixture diluted with water, extracted with DCM and the organic layer washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduce pressure to give the title compound (4.8 g, 90%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.71-7.49 (m, 3H), 3.88 (s, 3H).

(b) 2-Bromo-3-fluorobenzohydrazide (A54)

[0571] To a solution of methyl 2-bromo-3-fluorobenzoate (A53) (4.8 g, 20.6 mmol) in EtOH (30 mL) was added hydrazine hydrate (80% in water, 16.0 g, 329 mmol) and the mixture was heated at 55° C. for 3 h. The mixture was returned to room temperature, poured into ice water and the resulting precipitate collected by filtration and dried under vacuum to give the title compound (3.2 g, 67%) as a white solid. LCMS-B (ES-API): rt 1.54 min, m/z 233.0, 235.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (br s, 1H), 7.52-7.40 (m, 2H), 7.20 (ddd, J=6.9, 2.0, 0.8 Hz, 1H), 4.53 (br s, 2H).

[0572] To a solution of 2-bromo-3-fluorobenzohydrazide (A54) (3.2 g, 13.7 mmol) in DMF (26.0 mL) was added Et.sub.3N (4.2 g, 41.2 mmol) and CDI (6.7 g, 41.2 mmol) and the mixture was heated at 40° C. for 3 h. The mixture was poured into water, extracted with DCM and the organic extract washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=5:1) to give the title compound (1.5 g, 43%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.9 (br s, 1H), 7.67-7.59 (m, 3H).

(d) 5-(3-Fluoro-2-vinylphenyl)-1,3,4-oxadiazol-2(3H)-one (A56)

[0573] To a solution of 5-(2-bromo-3-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one (A55) (600.0 mg, 2.33 mmol) and tributyl(vinyl)stannane (2.2 g, 6.98 mmol) in toluene (9 mL) was added Pd(PPh.sub.3).sub.4 (265.8 mg, 0.23 mmol) and the mixture was heated at reflux under N.sub.2 for 16 h. The mixture was poured into water (20 mL), extracted with EtOAc (9 mL×3) and the combined organic extracts washed with water (9 mL×2), brine (9 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether/EtOAc=50:1 to 10:1) to give the title compound (420 mg, 87%) as a white solid. LCMS-B (ES-API): rt 3.307 min, m/z 207.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.7 (br s, 1H), 7.60-7.56 (m, 1H), 7.51-7.44 (m, 2H), 6.99 (dd, J=17.9, 11.8 Hz, 1H), 5.78 (ddd, J=17.9, 2.6, 1.6 Hz, 1H), 5.67 (dt, J=11.8, 1.8 Hz, 1H).

(e) 2-Fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzaldehyde (A57)

[0574] A solution of 5-(3-fluoro-2-vinylphenyl)-1,3,4-oxadiazol-2(3H)-one (A56) (200 mg, 0.97 mmol) in DCM/MeOH (6.0 mL/6.0 mL) was cooled to −70° C. and bubbled with O.sub.3 gas until a pale blue color persisted. Dimethyl sulfide (746 mg, 12.0 mmol) was added, the mixture was returned to room temperature and then stirred for 1 h. The mixture was concentrated under reduced pressure to give the title compound (250 mg) as a yellow oil, which was used directly in the next step without further purification. LCMS-B (ES-API): rt 2.69 min, m/z 207.0 [M−H].sup.−

(f) 1,1′-(Ethane-1,2-diyl)bis(2-(2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (49)

[0575] A solution of 2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzaldehyde (A57) (crude material from previous step, 250 mg), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (120 mg, 0.41 mmol) and Oxone® (304 mg, 0.49 mmol) in DMF (3.0 mL) was stirred at room temperature for 1 h. The mixture was poured into water (10.0 mL) and the resulting precipitate collected by filtration and purified by prep-HPLC (Agilent YMC-C18, 5 μm, 150×20 mm column, eluting with a gradient of ACN in water with 0.1% formic acid, at a flow rate of 15.0 mL/min) to give the title compound (9.0 mg, 2.4% over two steps) as a white solid. NMR analysis showed the presence of approximately 0.05 equivalents of formic acid. LCMS-B (ES-API): rt 2.63 min, m/z 765.2 [M+H]+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90-7.62 (m, 6H), 7.62-7.46 (m, 5H), 7.28-7.15 (m, 2H), 7.00-6.92 (m, 1H), 4.67-4.54 (m, 2H), 4.29 (s, 6H), 4.18-4.05 (m, 2H).

Example 26: 1,1-(Ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (50)

[0576] ##STR00056## ##STR00057##

(a) Methyl 2-bromo-5-chloro-3-fluorobenzoate (A58)

[0577] To a solution of 2-bromo-5-chloro-3-fluorobenzoic acid (A24) (4.0 g, 15.8 mmol) in DMF (52 mL) was added CH.sub.3I (4.5 g, 31.6 mmol) and K.sub.2CO.sub.3 (6.4 g, 47.4 mmol) and the mixture was stirred at room temperature for 30 min. The mixture was diluted with water, extracted with EtOAc and the organic layer washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 50:1) to give the title compound (3.97 g, 95%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.87 (dd, J=8.6, 2.4 Hz, 1H), 7.70 (dd, J=2.3, 1.5 Hz, 1H), 3.88 (s, 3H).

(b) 2-Bromo-5-chloro-3-fluorobenzohydrazide (A59)

[0578] To a solution of methyl 2-bromo-5-chloro-3-fluorobenzoate (A58) (1.5 g, 5.6 mmol) in EtOH (10 mL) was added hydrazine hydrate (80% in water, 5.6 g, 89.5 mmol) and the mixture was heated at 55° C. for 2 h. The mixture was returned to room temperature, poured into ice water and the resulting precipitate collected by filtration and dried under vacuum to give the title compound as a white solid (1.4 g, 93%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.71 (br s, 1H), 7.74 (dd, J=8.7, 2.4 Hz, 1H), 7.34 (dd, J=2.4, 1.3 Hz, 1H), 4.55 (br s, 2H).

[0579] To a solution of 2-bromo-5-chloro-3-fluorobenzohydrazide (A59) (1.4 g, 5.6 mmol) in DMF (15.0 mL) was added CDI (2.5 g, 15.7 mmol) and Et.sub.3N (1.6 g, 15.7 mmol) and the mixture was heated at 40° C. overnight under N.sub.2. The mixture was cooled to room temperature, poured into water and extracted with DCM. The organic extract was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=50:1 to 10:1) to give the title compound (630 mg, 42%) as a white solid. LCMS-B (ES-API): rt 3.543 min; m/z 292.9, 294.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (dd, J=8.6, 2.4 Hz, 1H), 7.70 (dd, J=2.0, 1.2 Hz, 1H).

(d) 5-(5-Chloro-3-fluoro-2-vinylphenyl)-1,3,4-oxadiazol-2(3H)-one (A61)

[0580] To a solution of 5-(2-bromo-5-chloro-3-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one (A60) (630 mg, 2.17 mmol) in toluene (7.0 mL) was added tributyl(vinyl)stannane (2.06 g, 6.5 mmol) and Pd(PPh.sub.3).sub.4 (375.3 mg, 0.325 mmol) and the mixture was heated at reflux under N.sub.2 overnight. The mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography (Pet. Ether to Pet. Ether/EtOAc=20:1) to give the title compound (380 mg, 73%) as a white solid. LCMS-B (ES-API): rt 3.656 min; m/z 241.0, 242.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.9 (s, 1H), 7.76 (dd, J=10.9, 2.1 Hz, 1H), 7.76 (dd, J=2.0, 0.8 Hz, 1H), 6.98 (dd, J=18.0, 12.0 Hz, 1H), 5.82-5.68 (m, 2H).

(e) 4-Chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzaldehyde (A62)

[0581] A solution of 5-(5-chloro-3-fluoro-2-vinylphenyl)-1,3,4-oxadiazol-2(3H)-one (A61) (380 mg, 1.58 mmol) in DCM/MeOH (1:1, 5.0 mL) was cooled to −78° C. and bubbled with O.sub.3 gas) until a pale blue color persisted. Dimethyl sulfide (490 mg, 7.9 mmol) was then added and the mixture was returned to room temperature and stirred for 1 h. The mixture was concentrated at 25° C. to give the title compound (200 mg) as a brown oil, which was used directly in the next step without further purification. LCMS-B (ES-API): rt 3.144 min; m/z 241.0, 243.0 [M−H].sup.−.

(f) 1,1′-(Ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (50)

[0582] A solution of 4-chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) benzaldehyde (A62) (crude material from previous step, 200 mg), 4,4′-(ethane-1,2-diylbis(azane diyl))bis(3-amino-2-methoxybenzamide) (I13) (87.5 mg, 0.23 mmol) and Oxone® (170 mg, 0.276 mmol) in DMF (1.0 mL) was stirred at room temperature for 1 h. The mixture was then diluted with water, freeze-dried and the residue purified by silica gel chromatography (DCM to DCM/MeOH=10:1) followed by prep-HPLC (Agilent YMC-C18, 5 μm, 150×20 mm column, eluting with a gradient of ACN in water with 0.1% formic acid, at a flow rate of 15.0 mL/min) to give the title compound (7.2 mg, 1.1% over 2 steps) as a white solid. LCMS-B (ES-API): rt 2.799 min; m/z 833.1, 835.1 [M+11]+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.73 (br s, 2H), 7.64 (s, 2H), 7.55-7.46 (m, 4H), 7.06 (d, J=8.6 Hz, 2H), 6.89 (br s, 2H), 4.50-4.39 (m, 2H), 4.33 (s, 6H), 4.15-4.04 (m, 2H).

Further Examples

[0583] The following example compounds were prepared by analogous methods.

TABLE-US-00012 Characterisation Structure Name data 19.1 and 19.2 [00058] embedded image 2,2′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(3-iodobenzoic acid) Mixture of atropisomers (meso and racemate) separated into two peaks (unassigned): Peak 1: 19.1 Peak 2: 19.2 19.1: LCMS-B (ES- API): rt 2.88 min, m/z 901.0 [M + H].sup.+. 19.2: LCMS-B (ES- API): rt 3.07 min, m/z 901.0 [M + H].sup.+. 20 [00059] embedded image 6,6′-(Ethane-1,2-diylbis(5- carbamoyl-7-fluoro-4- methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(3-chlorobenzoic acid) LCMS-B (ES- API): rt 2.77 min, m/z 753.3, 755.3 [M + H].sup.+. 21 [00060] Dimethyl 6,6′-(ethane-1,2- diylbis(5-carbamoyl-4- methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(2- bromobenzoate) LCMS-B (ES- API): rt 3.37 min, m/z 833.1, 835.1 [M + H].sup.+. 22 [00061] embedded image 2,2′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(3-chlorobenzoic acid) Mixture of three atropisomers (meso and racemate) LCMS-B (ES- API): rt 2.75 & 2.92 min, m/z 717.1, 719.1 [M + H].sup.+. 23 [00062] 1,1′-(Ethane-1,2-diyl)bis(2- (2-chloro-6-(2H-tetrazol-5- yl)phenyl)-4-methoxy-1H- benzo[d]imidazole-5- carboxamide) Mixture of atropisomers separated (meso and racemate): Peak 2 (unassigned stereochemistry) LCMS-B (ES- API): rt 2.87 min, m/z 765.2, 767.2 [M + H].sup.+. 24 [00063] embedded image 1,1′-(Ethane-1,2-diyl)bis(2- (4-chloro-2-(2H-1,2,3- triazol-4-yl)phenyl)-4- methoxy-1H- benzo[d]imidazole-5- carboxamide) LCMS-B (ES- API): rt 2.77 min, m/z 763.4, 765.4 [M + H].sup.+. 25 [00064] 6,6′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(3-methylbenzoic acid) LCMS-B (ES- API): rt 2.48 min, m/z 677.3 [M + H].sup.+. 26 [00065] embedded image 2,2′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(4-methylbenzoic acid) LCMS-B (ES- API): rt 2.61 min, m/z 677.3 [M + H].sup.+. 27 [00066] 6,6′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(3-fluorobenzoic acid) LCMS-B (ES- API): rt 2.48 min, m/z 685.2 [M + H].sup.+. 28 [00067] embedded image 2,2′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(4-fluorobenzoic acid) LCMS-B (ES- API): rt 2.56 min, m/z 685.2 [M + H].sup.+. 29.1 and 29.2 [00068] 2,2′-(Ethane-1,2-diylbis(5- carbamoyl-1H- benzo[d]imidazole-1,2- diyl))bis(3-bromobenzoic acid) Mixture of atropisomers (meso and racemate) separated into two peaks (unassigned): Peak 1: 29.1 Peak 2: 29.2 29.1: LCMS-A (ES- API): rt 0.49 min, m/z 745.0, 747.0 [M + H].sup.+. 29.2: LCMS-A (ES- API): rt 0.58 min, m/z 744.9, 746.9 [M + H].sup.+. 30 [00069] embedded image 3,3′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))diisonicotinic acid LCMS-B (ES- API): rt 3.09 min, m/z 651.2 [M + H].sup.+. 31 [00070] 2,2′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(5-chloronicotinic acid) LCMS-B (ES- API): rt 2.85 min, m/z 719.3, 721.3 [M + H].sup.+. 32 [00071] embedded image 1,1′-(Ethane-1,2-diyl)bis(2- (4-chloro-2-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3- yl)phenyl)-4-methoxy-1H- benzo[d]imidazole-5- carboxamide) LCMS-B (ES- API): rt 2.77 min, m/z 797.4, 799.4 [M + H].sup.+. 33 [00072] 6,6′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(3-ethylbenzoic acid) LCMS-B (ES- API): rt 2.75 min, m/z 705.4 [M + H].sup.+. 34 [00073] embedded image (E)-6,6′-(But-2-ene-1,4- diylbis(5-carbamoyl-4- methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(3-chlorobenzoic acid) LCMS-B (ES- API): rt 3.04 min, m/z 743.3, 745.3 [M + H].sup.+. 35 [00074] 6,6′-(Propane-1,3- diylbis(5-carbamoyl-4- methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(3-chlorobenzoic acid) LCMS-B (ES- API): rt 2.92 min, m/z 731.3, 733.3 [M + H].sup.+. 36 [00075] embedded image 6,6′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(2-bromobenzoic acid) LCMS-B (ES- API): rt 2.53 min, m/z 805.0, 807.0 [M + H].sup.+. 37 [00076] 1,1′-(Ethane-1,2-diyl)bis(2- (3,4-dichloro-2-(2H- tetrazol-5-yl)phenyl)-4- methoxy-1H- benzo[d]imidazole-5- carboxamide) LCMS-B (ES- API): rt 2.73 min, m/z 833.1, 835.1 [M + H].sup.+. 38 [00077] embedded image 6,6′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(3- (trifluoromethyl)benzoic acid) LCMS-B (ES- API): rt 2.90 min, m/z 785.2 [M + H].sup.+. 39 [00078] 6,6′-(Ethane-1,2-diylbis(5- carbamoyl-1H- benzo[d]imidazole-1,2- diyl))bis(3-chlorobenzoic acid) LCMS-B (ES- API): rt 3.47 min, m/z 657.1, 659.1 [M + H].sup.+. 40 [00079] embedded image 1,1′-(Ethane-1,2-diyl)bis(2- (3-chloro-2-(2H-tetrazol-5- yl)phenyl)-4-methoxy-1H- benzo[d]imidazole-5- carboxamide) LCMS-B (ES- API): rt 2.58 min, m/z 765.2, 787.2 [M + H].sup.+. 41 [00080] 6,6′-(Ethane-1,2-diylbis(5- carbamoyl-4-methoxy-1H- benzo[d]imidazole-1,2- diyl))bis(3- methoxybenzoic acid) LCMS-B (ES- API): rt 2.36 min, m/z 709.2 [M + H].sup.+. 51 [00081] embedded image 2-(5-Carbamoyl-1-(2-(5- carbamoyl-2-(2-carboxy-4- cyanophenyl)-4-methoxy- 1H-benzo[d]imidazol-1 - yl)ethyl)-4-methoxy-1H- benzo[d]imidazol-2-yl)-5- cyanobenzoic acid LCMS-B (ES- API): rt 2.215 min, m/z 699.3 [M + H].sup.+. 52 [00082] Methyl 2-(5-carbamoyl-1- (2-(5-carbamoyl-2-(4- cyano-2- (methoxycarbonyl)phenyl)- 4-methoxy-1H- benzo[d]imidazol-1- yl)ethyl)-4-methoxy-1H- benzo[d]imidazol-2-yl)-5- cyanobenzoate LCMS-B (ES- API): rt 2.817 min, m/z 727.4 [M + H].sup.+.

[0584] Assays

[0585] Compounds disclosed herein are tested for activity as modulators of STING in the following assays. Each assay is designed to test different aspects of potential interaction of the compounds with STING. Therefore, compounds are considered active provided they demonstrate binding or modulation in any one (or more) of these assays.

[0586] Protein Production and Purification

[0587] Biophysical experiments were performed with three different recombinant human STING protein variants designated according to allelic nomenclature of Yi et al., (2013). Codon optimized DNA sequences (for expression in Escherichia coli) encoding amino acid residues 149 to 345 (Swiss Prot Q86WV6) of human STING (WT), human STING (HAQ) and human STING (R232H) were synthesised by GenScript USA Inc (Piscataway, N.J., USA). These were ligated into a modified pET43a E. coli expression vector designed to encode N-terminal His tag followed by tobacco etch virus protease (TEV) cleavage site and a STING gene sequence. The resulting protein sequences for the three allelic variants are listed below:

TABLE-US-00013 His-TEV-hSTING(WT) MGHHHHHHGTENLYFQGSE.sup.149KGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNOHYNNL LRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENG QRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLI AYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGS.sup.345 His-TEV-hSTING(R232H) MGHHHHHHGTENLYFQGSE.sup.149SKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNL LRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVYSNSIYELLENG QRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLI AYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGS.sup.345 His-TEV-hSTING(HAQ) MGHHHHHHGTENLYFQGSE.sup.149KGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNL LRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTADRAGIKDRVYSNSIYELLENG QRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCQTLEDILADAPESQNNCRLI AYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGS.sup.345

[0588] To produce recombinant human STING proteins, expression plasmid encoding above-described constructs were transformed into E. coli BL21 DE3 strain and grown with shaking at 37° C. in 2×1 L volumes of Terrific broth (TB) supplemented with 100 μg/ml Ampicillin until OD.sub.600 of 0.8 was reached. Cultures were then cooled to 16° C. and protein expression induced by the addition of isopropyl β-D-1-thiogalactopyranoside to a final concentration of 0.5 mM and the cultures shaken overnight for further 16 hours. Following expression, cell cultures were centrifuged at 5000×g for 20 min and cell pellet stored frozen at −70° C.

[0589] Protein purification was initiated by thawing the cell pellet in Lysis buffer (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 2 mM MgCl.sub.2, 10 mM imidazole, 0.5 mg/ml lysozyme, benzonase endonuclease [EMD Millipore], 1 mM PMSF, complete protease inhibitor tablets EDTA-free [Roche]) using a ratio of 7 ml of buffer per 1 g of cells. Cells were further lysed by 3 passes through an ice cooled Avestin C.sub.5 cell crusher and then centrifuged at 48,000×g at 4° C. Supernatant (cell lysate) was filtered through a 5 μm filter and loaded onto 5 mL HiTrap IMAC Sepharose FF column (GE Healthcare) pre-equilibrated with IMAC wash buffer 1 (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 10 mM imidazole) using Profinia Affinity chromatography purification system (Bio-Rad). The IMAC column was then sequentially washed with IMAC Wash buffer 1 and IMAC Wash buffer 2 (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 20 mM Imidazole) and bound His-TEV-hSTING protein eluted with IMAC Elution buffer (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 250 mM Imidazole). IMAC-eluted protein was further purified by passing through a HiLoad 26/60 Superdex 75 column pre-equilibrated in storage buffer (25 mM Tris-HCl, pH 8.0, 150 mM NaCl, 5 mM DTT 0.02% [w/v] sodium azide). Finally, hSTING protein was concentrated to 2 mg/ml using Amicon Ultra centrifugal filter unit (Utra-15 MWCO 10 kDa), flash-frozen in liquid nitrogen and stored in −70° C. freezer.

[0590] Differential Scanning Fluorimetry (DSF)

[0591] Differential scanning fluorimetry (DSF) is a rapid screening method for identifying low-molecular-weight ligands that bind and, in doing so, stabilize (or sometimes destabilize) purified proteins (Niesen 2007). DSF monitors thermal unfolding of protein in the presence of a fluorescent dye and is typically performed using a real-time PCR instrument. The temperature at which a protein unfolds is measured by an increase in the fluorescence of a dye with affinity for hydrophobic parts of the protein that are gradually being exposed during unfolding. The fluorescence of the dye is quenched in aqueous environments, but when the dye associates with hydrophobic sites on unfolded protein, its fluorescence increases. The fluorescence intensity is plotted as a function of the temperature, generating a sigmoidal curve that can be described by a two-state transition. The inflection point of the transition curve (Tm) is calculated using simple equations such as that of Boltzmann.

[0592] Thermal stability of STING protein (with and without bound ligand) was measured using previously described methodology (Seabrook & Newman, 2013), with samples tested in triplicate using 96-well PCR microplate (AB Gene, ABGAB-0600/W). In a final volume of 20 μL, 2 μM protein in 1×HBS buffer (50 mM HEPES, pH 7.4, 150 mM NaCl) was mixed with SYPRO Orange dye (Sigma-Aldrich S5692, final reaction mix dilution 1:1200) and a compound (final concentration at 100 μM). Sealed plates were placed into Bio-Rad CFX96/C1000 thermocycler and FRET scanning mode (λ.sup.excitation of 490 nm and reads at a λ.sup.emission of 570 nm). Melting curves were recorded from 20° C. to 100° C. in 0.5° C. increments every 30 seconds with a read at each increment. Data were analysed using “Meltdown analysis” protocol described by Rosa (2015). The melting temperature (T.sub.m) obtained for STING protein alone (1%[v/v] DMSO) was subtracted from T.sub.m obtained for protein incubated with ligand to generate ΔT.sub.m values listed in the table below. DSF data was generated for each compound against 3 different STING protein variants—human STING (WT), human STING (HAQ) and human STING (R232H).

TABLE-US-00014 DSF huSTING DSF huSTING (HAQ) (WT) Example ΔTm (° C.) ΔTm (° C.) 1 9.44 5.07 2 −3.48 −6.94 3 2.66 −0.02 4 7.23 3.28 5 6.04 1.33 6 5.44 0.94 7 5.88 −2.49 8 23.22 6.38 9 11.31 5.06 10 18.43 9.63 11 22.12 10.62 12 28.33 4.56 14 9.15 4.74 15 4.78 −0.91 16 17.24 7.95 17 11.95 3.05 18 19.08 2.40 19.1 31.74 19.29 19.2 21.66 6.58 20 3.69 −3.00 21 5.83 2.33 22 28.16 16.96 23 29.21 14.96 24 −0.08 −3.16 25 −15.64 −18.45 26 6.33 1.13 27 6.17 2.62 28 −2.19 −6.60 29.1 7.46 −0.07 29.2 −5.65 −6.70 30 2.14 0.29 31 3.98 0.18 32 3.99 0.51 33 4.06 1.17 34 0.49 −2.39 35 1.28 −2.51 36 5.24 2.04 37 2.80 −0.24 38 3.68 0.38 39 0.86 −4.35 40 −1.74 −7.45 41 4.52 1.09 42 6.3 2.04 43 22.22 9.87 44 13.05 0.88 45 1.24 −0.34 46 28.61 14.38 48 25.49 11.8 49 21.32 10.22 50 26.42 12.47 51 1.6 −0.85

[0593] Surface Plasmon Resonance (SPR)

[0594] Binding interactions of ligands with STING proteins were quantified using Surface Plasmon Resonance (SPR) with a minimally biotinylated STING protein immobilized on a streptavidin chip surface. In this manner highly active STING protein surfaces were obtained that were not compromised by a low pH required for an amine coupling method. Minimal biotinylation of purified huSTING proteins was performed using a previously described methodology (Chhabra 2012). Briefly, approximately 20 nmol of recombinant STING protein in 1×TBS buffer (25 mM Tris-HCl, pH 7.5, 150 mM NaCl, 5 mM DTT) was mixed with of EZ-Link™ Sulfo-NHS-LC-LC-Biotin (Thermofisher Scientific, cat #21338) at a molar ratio of 1 to 0.6 and incubated on ice for 2 hours. To remove any unreacted biotin reagent, protein/biotin mixture was passed through a Superdex 75 (10/300 GL) column equilibrated with 10 mM HEPES, pH7.4, 150 mM NaCl, 5 mM DTT, 5%[v/v] glycerol. A protein peak containing biotinylated huSTING protein was collected and stored in aliquots at −80° C.

[0595] Streptavidin was simultaneously immobilized in all four channels of a CM5 sensor chip docked in a Biacore instrument (either Biacore S200 or Biacore T200, GE Healthcare) as described previously (Zender 2013). Minimally biotinylated STING protein was captured onto a streptavidin coated chip surface at 8° C. in SPR binding buffer (50 mM HEPES, pH 7.4, 150 mM NaCl, 2%[v/v] DMSO) by gradually injecting in a single channel at a constant flow-rate of 2 μL/min until desired capture level was achieved, typically 3000 to 7000 RU (1 RU=1 pg/mm.sup.2).

[0596] All binding experiments were performed at 8° C. in SPR binding buffer. To determine binding affinity, compound interaction with immobilized STING protein was analysed using dose-response experiments. Fresh 10 mM DMSO solutions of compound were diluted directly into SPR binding buffer typically to a concentration of 50 μM and then further diluted 2-fold or 3-fold aiming for either a 5- or 7-point concentration series range. Each ligand concentration series was injected at a constant flow rate of 60 μL/min with a 90 second association and a 180 second dissociation time. These were modified for compounds with longer residence times, so that curves could reach steady-state, or so that compound would be fully dissociated before the subsequent injection. Where appropriate, tighter-binding compounds (roughly K.sub.D<1 uM) were tested using a single-cycle kinetics format (Karlsson 2006), with long association and dissociation times (typically 450 s and 1800 s, respectively).

[0597] Scrubber 2 (www.biologic.com.au) was utilized for data processing, where signals were referenced against the blank surface (streptavidin+D-biotin) and further corrected for DMSO refractive index change and then “double-referenced” using a buffer-blank injection (Papalia 2006). Responses were fitted to either a 1:1 steady-state affinity model or a 1:1 kinetic model (that included a mass-transport component), available within Scrubber.

TABLE-US-00015 SPR (HAQ) K.sub.D Example (μM) 1 16.6 2 67 3 >10 4 28.6 5 19.3 6 11.9 9 2.66 10 0.183 11 0.078 15 6.34 16 0.166 17 0.416 18 0.144 19.1 0.002 20 12.8 21 1.09 22 0.002 23 0.002 24 22 25 19.3 26 32.5 29.1 0.936 30 90 31 55 32 90 33 78 34 26 35 35 37 0.200 38 >100 39 300 40 64 41 83 42 14.8 43 0.096 44 0.423 45 28.9 46 0.025 48 0.030 49 0.031 50 0.014 SPR (WT) K.sub.D Example (μM) 1 200 2 80 3 700 4 >10 5 30 6 40 9 40 10 5.86 11 1.08 15 1000 16 1.52 17 9.5 18 2.01 19.1 0.034 20 96 21 5.380 22 0.077 23 0.043 24 102 25 250 26 >40 29.1 33 30 126 31 88 32 >80 33 107 34 74 35 >100 36 58 38 >100 40 180 41 200 42 139.1 43 1.79 44 11.1 45 29.6 46 0.413 48 0.512 49 0.755 50 0.359

[0598] THP-1 Reporter Cell Line Assays

[0599] THP-1 STING Lucia ISG cells (InvivoGen #thpI-isg) were cultured in RPMI-1640 containing 2 mM L-glutamine, 25 mM HEPES, 100 μg/mL Normocin (InvivoGen) and 10% heat-inactivated FBS. Cells were seeded at a density of 7×10.sup.5 cells/mL, maintained at 37° C./5% CO.sub.2, and passaged every 3-4 days. Selection pressure was maintained by the addition of 100 μg/mL Zeocin every second passage.

[0600] Assay conditions: cells were harvested and resuspended at a concentration of 5×10.sup.5 cells/mL in fresh growth media. Of this cell preparation 20 μL per well was dispensed into 384 well cell culture plates (Greiner, #781098X) and incubated at 37° C./5% CO.sub.2 for 2 hours. Concentration Response Curves (commonly 11 doses) were prepared by 2.5 fold serial dilution starting from 10 mM compound stock solution in DMSO. Compound dilutions were transferred into the cell culture plates using a pintool (0.1 μL transfer), control wells were matched for DMSO. Positive control wells received ML RR-S2 CDA (Med Chem Express HY12885B) in 5 μL of media to a final concentration of 40 μM. All other wells received additional 5 μL of media only to equalise volume. The plates were incubated for 24 h at 37° C./5% CO.sub.2.

[0601] For the detection step, QUANTI-Luc (InvivoGen #rep-qlc1) was prepared according to manufacturer's instruction and 10 μL were added per well to the culture plates. Plates were shaken for ten seconds on an orbital shaker and left in the dark at room temperature for two minutes, before luminescence was read on a Perkin Elmer Envision plate reader.

[0602] Data analysis: Luminescence raw data was normalised % activity relative to the signal of the positive control wells and negative control wells which were not treated with compound. The following formula was used to calculate normalised % activity from raw signals:

% activity=(sample−negative)/(positive−negative)

[0603] The THP-1 STING Lucia ISG cell EC.sub.50 provides an assessment of activity at the human HAQ isoform of STING. For assessing compound activity against the WT human STING isoform, an equivalent method was conducted where the cells used were THP-1-Dual KI-hSTING-R232 (InvivoGen #thpd-r232).

TABLE-US-00016 EC.sub.50 THP-1 EC.sub.50 THP-1 STING Lucia Dual KI-hSTING- ISG cells R232 cells Example (μM) (μM) 1 1.07 0.895 2 >40 >40 3 >40 >40 4 15.9 32.5 5 24.8 6.4 6 0.902 0.936 7 1.55 1.43 8 0.540 0.426 9 0.777 0.715 10 1.59 1.39 11 0.830 0.683 12 2.65 2.55 13 >40 >40 14 1.31 1.99 15 2.56 2.46 16 0.738 0.840 17 0.290 0.360 18 0.326 0.566 19.1 0.297 0.232 19.2 14.9 11.7 20 1.30 2.78 21 1.49 1.63 22 1.53 1.45 23 2.50 2.47 24 2.67 4.19 25 2.96 3.20 26 3.38 3.22 27 11.25 10.52 28 12.6 >40 29.1 18.4 9.85 29.2 >40 >40 30 39.1 28.9 31 >40 >40 32 >40 29.7 33 >40 >40 34 >40 >40 35 >40 >40 36 >40 >40 37 >40 >40 38 >40 >40 39 >40 >40 40 >40 >40 41 >40 >40 42 3.211 4.385 43 0.5743 0.4401 44 0.5576 0.3797 45 6.788 3.248 46 0.2175 0.1946 47 0.497 0.5493 48 0.4148 0.2694 49 0.136 0.1905 50 0.1736 0.03117

STATEMENTS OF INVENTION

[0604] 1. A compound of formula I:

##STR00083##

wherein:
Y is either (CH.sub.2).sub.n, where n is from 2 to 4, or —CH.sub.2—CH═CH—CH.sub.2—;
R.sup.1 and R.sup.11 are independently selected from the group consisting of: —C(═O)OH, —C(═O)OR.sup.P1, tetrazolyl, Br, F, oxo-oxadiazolyl and

##STR00084##

(2H-triazol-4-yl), where R.sup.P1 is selected from methyl and ethyl;
A.sup.1 is CR.sup.A or N;
A.sup.2 is CR.sup.B or N;
A.sup.3 is CR.sup.C or N;
A.sup.4 is CR.sup.D or N;
where no more than two of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 may be N;
one, two or three of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, I, Me, Et, CF.sub.3, cyclopropyl, cyano, OMe, OEt, CH.sub.2OH, CH.sub.2OMe and OH;
the remainder of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are H;
A.sup.11 is CR.sup.AA or N;
A.sup.12 is CR.sup.BB or N;
A.sup.13 is CR.sup.CC or N;
A.sup.14 is OR.sup.DD or N;
where no more than two of A.sup.11, A.sup.12, A.sup.13 and A.sup.14 may be N;
one, two or three of R.sup.AA, R.sup.BB, R.sup.CC and R.sup.DD (if present) are selected from H, F, Cl, Br, I, Me, Et, CF.sub.3, cyclopropyl, cyano, OMe, OEt, CH.sub.2OH, CH.sub.2OMe and OH;
the remainder of R.sup.AA, R.sup.BB, R.sup.CC and R.sup.DD, (if present) are H;
R.sup.C1, R.sup.C3 and R.sup.C4 are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF.sub.3, CH.sub.2OH, CH.sub.2OMe, C.sub.2-4 alkenyl and C.sub.5heterocyclyl;
R.sup.C11, R.sup.C13 and R.sup.C14 are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF.sub.3, CH.sub.2OH, CH.sub.2OMe, C.sub.2-4alkenyl and C.sub.5heterocyclyl.

[0605] 2. A compound according to statement 1, wherein A.sup.11=A1, A.sup.12=A.sup.2, A.sup.13=A.sup.3, A.sup.14=A.sup.4, R.sup.C11=R.sup.C1, R.sup.C13=R.sup.C3, R.sup.C14=R.sup.C4, R.sup.11=R.sup.1.

[0606] 3. A compound according to statements 1 or 2, wherein A.sup.1 is CR.sup.A. 4. A compound according to statements 1 or 2, wherein A.sup.1 is N.

[0607] 5. A compound according to any one of statements 1 to 4, wherein A.sup.2 is CR.sup.B.

[0608] 6. A compound according to any one of statements 1 to 4, wherein A.sup.2 is N.

[0609] 7. A compound according to any one of statements 1 to 6, wherein A.sup.3 is CR.sup.C.

[0610] 8. A compound according to any one of statements 1 to 6, wherein A.sup.3 is N.

[0611] 9. A compound according to any one of statements 1 to 6, wherein A.sup.4 is CR.sup.D.

[0612] 10. A compound according to any one of statements 1 to 6, wherein A.sup.4 is N.

[0613] 11. A compound according to statements 1 or 2, wherein A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, A.sup.3 is CR.sup.C, and A.sup.4 is CR.sup.D.

[0614] 12. A compound according to statements 1 or 2, wherein one of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are N.

[0615] 13. A compound according to statements 1 or 2, wherein two of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are N.

[0616] 14. A compound according to any one of statements 1 to 13, wherein A.sup.11 is CR.sup.AA.

[0617] 15. A compound according to any one of statements 1 to 13, wherein A.sup.11 is N.

[0618] 16. A compound according to any one of statements 1 to 15, wherein A.sup.12 is CR.sup.BB.

[0619] 17. A compound according to any one of statements 1 to 15, wherein A.sup.12 is N.

[0620] 18. A compound according to any one of statements 1 to 17, wherein A.sup.13 is CR.sup.CC.

[0621] 19. A compound according to any one of statements 1 to 17, wherein A.sup.13 is N.

[0622] 20. A compound according to any one of statements 1 to 19, wherein A.sup.14 is CR.sup.DD.

[0623] 21. A compound according to any one of statements 1 to 19, wherein A.sup.14 is N.

[0624] 22. A compound according to any one of statements 1 to 13, wherein A.sup.11 is CR.sup.AA, A.sup.2 is CR.sup.BB, A.sup.13 is CR.sup.CC, and A.sup.14 is CR.sup.DD.

[0625] 23. A compound according to any one of statements 1 to 13, wherein one of A.sup.11, A.sup.12, A.sup.13 and A.sup.14 are N.

[0626] 24. A compound according to any one of statements 1 to 13, wherein two of A.sup.11, A.sup.12, A.sup.13 and A.sup.14 are N.

[0627] 25. A compound according to any one of statements 1 to 13, wherein the compound is of formula IIIb:

##STR00085##

[0628] 26. A compound according to any one of statements 1 to 13, wherein the compound is of formula IIIc:

##STR00086##

[0629] 27. A compound according to any one of statements 1 to 13, wherein the compound is of formula IIId:

##STR00087##

[0630] 28. A compound according to any one of statements 1 to 13, wherein the compound is of formula IIIe:

##STR00088##

[0631] 29. A compound according to any one of statements 1 to 28, wherein one, two or three of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe, the remainder (if present) are H.

[0632] 30. A compound according to any one of statements 1 to 28, wherein one, two or three of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl and OMe, the remainder (if present) are H.

[0633] 31. A compound according to any one of statements 1 to 28, wherein one, two or three of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3 and OMe, the remainder (if present) are H.

[0634] 32. A compound according to any one of statements 1 to 31, wherein R.sup.A (if present) is selected from H and F.

[0635] 33. A compound according to any one of statements 1 to 32, wherein R.sup.B (if present) is selected from H, F and Cl.

[0636] 34. A compound according to statement 33, wherein R.sup.B (if present) is selected from H and Cl.

[0637] 35. A compound according to any one of statements 1 to 34, wherein R.sup.C (if present) is selected from H, F and Cl.

[0638] 36. A compound according to any one of statements 1 to 35, wherein R.sup.D (if present) is selected from H, F and Cl.

[0639] 37. A compound according to statement 11, wherein R.sup.A, R.sup.B, R.sup.C and R.sup.D are selected from one of the following combinations:

TABLE-US-00017 Combination R.sup.A R.sup.B R.sup.C R.sup.D 1 F H H H 2 H Br H H 3 H Cl H H 4 F Cl H H 5 H H H Br 6 H H Cl H 7 H F F H 8 H H H H 9 CF CH CF CH 10 CF CH CCl CH 11 CBr CH CH CH 12 CCl CH CH CH 13 N CH CCl CH 14 CH CCl CCl CH 15 CH CF CH CH 16 CH CMe CH CH 17 CH N CH CH 18 CH CH CBr CH 19 CH CH CCF.sub.3 CH 20 CH CH CEt CH 21 CH CH CF CH 22 CH CH CMe CH 23 CH CH C—OMe CH 24 CH CH CCl CCl 25 CH CH CH CF 26 CH CH CH C—OMe 27 CH CH CH N 28 Cl CH CH CH 29 CH CH CCN CH 30 CBr CH CCl CH

[0640] 38. A compound according to statement 37, wherein R.sup.A, R.sup.B, R.sup.C and R.sup.D are selected from combinations 1, 3, 6 and 9.

[0641] 39. A compound according to any one of statements 1 to 38, wherein one, two or three of R.sup.AA, R.sup.BB, R.sup.CC and R.sup.DD, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe, the remainder (if present) are H.

[0642] 40. A compound according to any one of statements 1 to 38, wherein one, two or three of R.sup.AA, R.sup.BB, R.sup.CC and R.sup.DD, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl and OMe, the remainder (if present) are H.

[0643] 41. A compound according to any one of statements 1 to 38, wherein one, two or three of R.sup.AA, R.sup.BB, R.sup.CC and R.sup.DD, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3 and OMe, the remainder (if present) are H.

[0644] 42. A compound according to any one of statements 1 to 41, wherein R.sup.AA (if present) is selected from H and F.

[0645] 43. A compound according to any one of statements 1 to 42, wherein R.sup.BB (if present) is selected from H, F and Cl.

[0646] 44. A compound according to statement 43, wherein R.sup.BB (if present) is selected from H and Cl.

[0647] 45. A compound according to any one of statements 1 to 44, wherein R.sup.CC (if present) is selected from H, F and Cl.

[0648] 46. A compound according to any one of statements 1 to 45, wherein R.sup.DD (if present) is selected from H, F and Cl.

[0649] 47. A compound according to statement 22, wherein R.sup.AA, R.sup.BB, R.sup.CC and R.sup.DD are selected from one of the following combinations:

TABLE-US-00018 Combination R.sup.AA R.sup.BB R.sup.CC R.sup.DD 1 F H H H 2 H Br H H 3 H Cl H H 4 F Cl H H 5 H H H Br 6 H H Cl H 7 H F F H 8 H H H H 9 CF CH CF CH 10 CF CH CCl CH 11 CBr CH CH CH 12 CCl CH CH CH 13 N CH CCl CH 14 CH CCl CCl CH 15 CH CF CH CH 16 CH CMe CH CH 17 CH N CH CH 18 CH CH CBr CH 19 CH CH CCF.sub.3 CH 20 CH CH CEt CH 21 CH CH CF CH 22 CH CH CMe CH 23 CH CH C—OMe CH 24 CH CH CCl CCl 25 CH CH CH CF 26 CH CH CH C—OMe 27 CH CH CH N 28 Cl CH CH CH 29 CH CH CCN CH 30 CBr CH CCl CH

[0650] 48. A compound according to statement 47, wherein R.sup.AA, R.sup.BB, R.sup.CC and R.sup.DD are selected R.sup.BB, from combinations 1, 3, 6 and 9.

[0651] 49. A compound according to any one of statements 1 to 48, wherein R.sup.C1, R.sup.C3 and R.sup.C4 are independently selected from H, Cl, F, Br, Me, OMe, cyano, CF.sub.3 and CH.sub.2OH.

[0652] 50. A compound according to any one of statements 1 to 49, wherein R.sup.C1, R.sup.C3 and R.sup.C4 are independently selected from H, Cl, F, CF.sub.3, OMe and CH.sub.2OH

[0653] 51. A compound according to any one of statements 1 to 50, wherein R.sup.C1, R.sup.C3 and R.sup.C4 are independently selected from H, F and OMe.

[0654] 52. A compound according to any one of statements 1 to 51, wherein two of R.sup.C1, R.sup.C3 and R.sup.C4 are H, and the other is selected from the defined groups, except H.

[0655] 53. A compound according to any one of statements 1 to 52, wherein one of R.sup.C1, R.sup.C3 and R.sup.C4 is H, and the other two are independently selected from the defined groups, except H.

[0656] 54. A compound according to any one of statements 1 to 52, wherein R.sup.C1, R.sup.C3 and R.sup.C4 are H.

[0657] 55. A compound according to any one of statements 1 to 48, wherein: [0658] R.sup.C1 is H; [0659] R.sup.C3 is H; and [0660] R.sup.C4 is F.

[0661] 56. A compound according to any one of statements 1 to 48, wherein: [0662] R.sup.C1 is OMe; [0663] R.sup.C3 is H; and [0664] R.sup.C4 is H or F.

[0665] 57. A compound according to any one of statements 1 to 56, wherein R.sup.C11=R.sup.C1, R.sup.C13=R.sup.C3 and R.sup.C14=R.sup.C4.

[0666] 58. A compound according to any one of statements 1 to 56, wherein R.sup.C11, R.sup.C13 and R.sup.C14 are independently selected from H, Cl, F, Br, Me, OMe, cyano, CF.sub.3 and CH.sub.2OH.

[0667] 59. A compound according to any one of statements 1 to 56, wherein R.sup.C11, R.sup.C13 and R.sup.C14 are independently selected from H, Cl, F, CF.sub.3, OMe and CH.sub.2OH.

[0668] 60. A compound according to any one of statements 1 to 56, wherein R.sup.C11, R.sup.C13 and R.sup.C14 are independently selected from H, F and OMe.

[0669] 61. A compound according to any one of statements 1 to 60, wherein two of R.sup.C11, R.sup.C13 and R.sup.C14 are H, and the other is selected from the defined groups, except H.

[0670] 62. A compound according to any one of statements 1 to 60, wherein one of R.sup.C11, R.sup.C13 and R.sup.C14 is H, and the other two are independently selected from the defined groups, except H.

[0671] 63. A compound according to any one of statements 1 to 60, wherein R.sup.C11, R.sup.C13 and R.sup.C14 are H.

[0672] 64. A compound according to any one of statements 1 to 56, wherein: [0673] R.sup.C11 is H; [0674] R.sup.C13 is H; and [0675] R.sup.C14 is F.

[0676] 65. A compound according to any one of statements 1 to 56, wherein: [0677] R.sup.C11 is OMe; [0678] R.sup.C13 is H; and [0679] R.sup.C14 is H.

[0680] 66. A compound according to any one of statements 1 to 65, wherein Y is (CH.sub.2).sub.n, where n is from 2 to 3.

[0681] 67. A compound according to any one of statements 1 to 65, wherein Y is (CH.sub.2).sub.2.

[0682] 68. A compound according to any one of statements 1 to 65, wherein Y is (CH.sub.2).sub.3.

[0683] 69. A compound according to any one of statements 1 to 65, wherein Y is (CH.sub.2).sub.4.

[0684] 70. A compound according to any one of statements 1 to 65, wherein Y is —CH.sub.2—CH═CH—CH.sub.2.sup.−.

[0685] 71. A compound according to any one of statements 1 to 70, wherein R.sup.1 and R.sup.11 are selected from —C(═O)OH, —C(═O)OR.sup.P1, tetrazolyl, oxo-oxadiazolyl and

##STR00089##

(2H-triazol-4-yl), where R.sup.P1 is selected from methyl and ethyl.

[0686] 72. A compound according to any one of statements 1 to 71, wherein R.sup.1 and R.sup.11 are selected from C(═O)OH, tetrazolyl and oxo-oxadiazolyl.

[0687] 73. A compound according to statement 71 or 72, wherein R.sup.1 and R.sup.11 are C(═O)OH.

[0688] 74. A compound according to statement 71 or 72, wherein R.sup.1 and R.sup.11 are tetrazolyl

[0689] 75. A compound according to statement 71 or 72, wherein R.sup.1 and R.sup.11 are oxo-oxadiazolyl.

[0690] 76. A compound according to any one of statements 1 to 76, wherein the compound is selected from any one of compounds 1-52.

[0691] 77. A compound according to any one of statements 1-75, wherein the compound is selected from any one of compounds 1-51.

[0692] 78. A compound according to any one of statements 1-77, wherein the compound is in the form of a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph or N-oxide, or a combination thereof in any ratio.

[0693] 79. A compound as defined in any one of statements 1 to 78, for use in a method of therapy.

[0694] 80. A pharmaceutical composition comprising a compound as defined in any one of statements 1 to 78, and a pharmaceutically acceptable excipient.

[0695] 81. A method of treatment or prevention of a disease ameliorated by the modulation of STING, comprising administering to a patient in need of treatment, a compound as defined in any one of statements 1 to 78, or a pharmaceutical composition according to statement 80.

[0696] 82. The use of a compound as defined in any one of statements 1 to 78, in the manufacture of a medicament for treating or preventing disease ameliorated by the modulation of STING.

[0697] 83. A compound as defined in any one of statements 1 to 78, or pharmaceutical composition according to statement 78 for use in the treatment or preventing of disease ameliorated by the modulation of STING.

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C07D235/20

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C07D401/14

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C07D403/14

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C07D413/14

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A61P35/00

HUMAN NECESSITIES

International classification

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C07D235/20

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C07D401/14

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C07D403/14

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C07D413/14

CHEMISTRY; METALLURGY

Abstract

Claims

Description